33 results on '"Villagra, Alejandro"'
Search Results
2. Tipifarnib-mediated suppression of T-bet-dependent signaling pathways.
- Author
-
Bai, Fanqi, Villagra, Alejandro, Zou, JianXiang, Painter, Jeffrey, Connolly, Kirby, Blaskovich, Michelle, Sokol, Lubomir, Sebti, Said, Djeu, Julie, Loughran, Thomas, Wei, Sheng, Sotomayor, Eduardo, and Epling-Burnette, Pearlie
- Subjects
- *
FARNESYLTRANSFERASE , *HISTONE acetylation , *INTERFERONS , *IMMUNOLOGICAL adjuvants , *LYMPHOPROLIFERATIVE disorders , *T cells , *TUMOR necrosis factors , *TRANSCRIPTION factors - Abstract
Large granular lymphocyte (LGL) leukemia is a chronic lymphoproliferative disease in which T-bet [T-box transcription factor 21 gene ( tbx21)] overexpression may play a pathogenic role. T-bet orchestrates the differentiation of mature peripheral T-cells into interferon-γ (IFN-γ) and tumor necrosis factor-α producing CD4+ T-helper type I (Th1) and CD8+ T cytotoxic cells that are necessary for antiviral responses. When IL-12 is produced by antigen-presenting cells, T-bet expression is induced, causing direct stimulation of ifng gene transcription while simultaneously acting as a transcriptional repressor of the IL4 gene, which then leads to Th1 dominance and T-helper type 2 differentiation blockade. Additionally, T-bet has been shown to regulate histone acetylation of the ifng promoter and enhancer to loosen condensed DNA, creating greater accessibility for other transcription factor binding, which further amplifies IFNγ production. We found that treatment with a farnesyltransferase inhibitor tipifarnib reduced Th1 cytokines in LGL leukemia patient T-cells and blocked T-bet protein expression and IL-12 responsiveness in T-cells from healthy donors. The mechanism of suppression was based on modulation of histone acetylation of the ifng gene, which culminated in Th1 blockade. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
3. The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance.
- Author
-
Villagra, Alejandro, Cheng, Fengdong, Wang, Hong-Wei, Suarez, Ildelfonso, Glozak, Michelle, Maurin, Michelle, Nguyen, Danny, Wright, Kenneth L, Atadja, Peter W, Bhalla, Kapil, Pinilla-Ibarz, Javier, Seto, Edward, and Sotomayor, Eduardo M
- Abstract
Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical 'decision' is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical 'decision' with substantial implications in autoimmunity, transplantation and cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
4. Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression.
- Author
-
Villagra, Alejandro, Ulloa, Natalia, Xiaohong Zhang, Zhigang Yuan, Sotomayor, Eduardo, and Seto, Edward
- Subjects
- *
HISTONE deacetylase , *CHOLESTEROL , *GENE expression , *ENZYMES , *RNA - Abstract
Invertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochemical functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that histone deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concentrations compared with parental cells. Extensive promoter analyses coupled with chromatin immunoprecipitation assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
5. Use of nanocrystalline diamond for microfluidic lab-on-a-chip
- Author
-
Khanna, Puneet, Villagra, Alejandro, Kim, Sangchae, Seto, Edward, Jaroszeski, Mark, Kumar, Ashok, and Bhansali, Shekhar
- Subjects
- *
DNA , *DIAMONDS , *NATIVE element minerals , *GENES - Abstract
Abstract: Nanocrystalline diamond (NCD) is an attractive building material for lab-on-a-chip devices due to its excellent biochemical and physical properties. In this paper we demonstrate that diamond exhibited the most resistance to non-specific DNA binding when compared to six other commonly used lab-on-a-chip building materials. This property is of critical importance to applications requiring high levels of purity and sensitivity. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
6. Chromatin Remodeling and Transcriptional Activity of the Bone-specific Osteocalcin Gene Require CCAAT/Enhancer-binding Protein β-dependent Recruitment of SWI/SNF Activity.
- Author
-
Villagra, Alejandro, Cruzat, Fernando, Carvallo, Loreto, Paredes, Roberto, Olate, Juan, van Wijnen, Andre J., Stein, Gary S., Lian, Jane B., Stein, Janet L., Imbalzano, Anthony N., and Montecino, Martin
- Subjects
- *
CHROMATIN , *TRANSCRIPTION factors , *GENES , *NUCLEASES , *CARRIER proteins , *PROTEIN binding , *BINDING sites - Abstract
Tissue-specific activation of the osteocalcin (OC) gene is associated with changes in chromatin structure at the promoter region. Two nuclease-hypersensitive sites span the key regulatory elements that control basal tissue-specific and vitamin D3-enhanced OC gene transcription. To gain understanding of the molecular mechanisms involved in chromatin remodeling of the OC gene, we have examined the requirement for SWI/SNF activity. We inducibly expressed an ATPase-defective BRG1 catalytic subunit that forms inactive SWI/SNF complexes that bind to the OC promoter. This interaction results in inhibition of both basal and vitamin D3-enhanced OC gene transcription and a marked decrease in nuclease hypersensitivity. We find that SWI/SNF is recruited to the OC promoter via the transcription factor CCAAT/enhancer-binding protein β, which together with Runx2 forms a stable complex to facilitate RNA polymerase II binding and activation of OC gene transcription. Together, our results indicate that the SWI/SNF complex is a key regulator of the chromatin-remodeling events that promote tissue-specific transcription in osteoblasts. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
7. Regulation of the Bone-Specific Osteocalcin Gene by p300 Requires Runx2/Cbfa1 and the Vitamin D[sub 3] Receptor but Not p300 Intrinsic Histone Acetyltransferase Activity.
- Author
-
Sierra, Jose, Villagra, Alejandro, Paredes, Roberto, Cruzat, Fernando, Gutierrez, Soraya, Javed, Amjad, Arriagada, Gloria, Olate, Juan, Imschenetzky, Maria, van Wijnen, Andre J., Lian, Jane B., Stein, Gary S., Stein, Janet L., and Montecino, Martin
- Subjects
- *
GENES , *TRANSCRIPTION factors , *BONE cells , *LABORATORY rats - Abstract
p300 is a multifunctional transcriptional coactivator that serves as an adapter for several transcription factors including nuclear steroid hormone receptors, p300 possesses an intrinsic histone acetyltransferase (HAT) activity that may be critical for promoting steroid-dependent transcriptional activation. In osteoblastic cells, transcription of the bone-specific osteocalcin (OC) gene is principally regulated by the Runx2/Cbfa1 transcription factor and is stimulated in response to vitamin D[sub 3] via the vitamin D[sub 3] receptor complex. Therefore, we addressed p300 control of basal and vitamin D[sub 3]-enhanced activity of the OC promoter. We find that transient overexpression of p300 results in a significant dose-dependent increase of both basal and vitamin D[sub 3]-stimulated OC gene activity. This stimulatory effect requires intact Runx2/Cbfa1 binding sites and the vitamin D-responsive element. In addition, by coimmunoprecipitation, we show that the endogenous Runx2/ Cbfa1 and p300 proteins are components of the same complexes within osteoblastic cells under physiological concentrations. We also demonstrate by chromatin immunoprecipitation assays that p300, Runx2/Cbfa1, and 1α,25-dihydroxyvitamin D[sub 3] receptor interact with the OC promoter in intact osteoblastic cells expressing this gene. The effect of p300 on the OC promoter is independent of its intrinsic HAT activity, as a HAT-deficient p300 mutant protein up-regulates expression and cooperates with P/CAF to the same extent as the wild-type p300. On the basis of these results, we propose that p300 interacts with key transcriptional regulators of the OC gene and bridges distal and proximal OC promoter sequences to facilitate responsiveness to vitamin D[sub 3]. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
8. Targeting HDAC6 improves anti-CD47 immunotherapy.
- Author
-
Gracia-Hernandez, Maria, Yende, Ashutosh S., Gajendran, Nithya, Alahmadi, Zubaydah, Li, Xintang, Munoz, Zuleima, Tan, Karen, Noonepalle, Satish, Shibata, Maho, and Villagra, Alejandro
- Subjects
- *
CELLULAR control mechanisms , *KILLER cells , *MYELOID cells , *IMMUNE checkpoint proteins , *IPILIMUMAB , *NATURAL immunity , *MICROPHTHALMIA-associated transcription factor - Abstract
Background: Cancer cells can overexpress CD47, an innate immune checkpoint that prevents phagocytosis upon interaction with signal regulatory protein alpha (SIRPα) expressed in macrophages and other myeloid cells. Several clinical trials have reported that CD47 blockade reduces tumor growth in hematological malignancies. However, CD47 blockade has shown modest results in solid tumors, including melanoma. Our group has demonstrated that histone deacetylase 6 inhibitors (HDAC6is) have immunomodulatory properties, such as controlling macrophage phenotype and inflammatory properties. However, the molecular and cellular mechanisms controlling these processes are not fully understood. In this study, we evaluated the role of HDAC6 in regulating the CD47/SIRPα axis and phagocytosis in macrophages. Methods: We tested the role of HDAC6is, especially Nexturastat A, in regulating macrophage phenotype and phagocytic function using bone marrow-derived macrophages and macrophage cell lines. The modulation of the CD47/SIRPα axis and phagocytosis by HDAC6is was investigated using murine and human melanoma cell lines and macrophages. Phagocytosis was evaluated via coculture assays of macrophages and melanoma cells by flow cytometry and immunofluorescence. Lastly, to evaluate the antitumor activity of Nexturastat A in combination with anti-CD47 or anti-SIRPα antibodies, we performed in vivo studies using the SM1 and/or B16F10 melanoma mouse models. Results: We observed that HDAC6is enhanced the phenotype of antitumoral M1 macrophages while decreasing the protumoral M2 phenotype. In addition, HDAC6 inhibition diminished the expression of SIRPα, increased the expression of other pro-phagocytic signals in macrophages, and downregulated CD47 expression in mouse and human melanoma cells. This regulatory role on the CD47/SIRPα axis translated into enhanced antitumoral phagocytic capacity of macrophages treated with Nexturastat A and anti-CD47. We also observed that the systemic administration of HDAC6i enhanced the in vivo antitumor activity of anti-CD47 blockade in melanoma by modulating macrophage and natural killer cells in the tumor microenvironment. However, Nexturastat A did not enhance the antitumor activity of anti-SIRPα despite its modulation of macrophage populations in the SM1 tumor microenvironment. Conclusions: Our results demonstrate the critical regulatory role of HDAC6 in phagocytosis and innate immunity for the first time, further underscoring the use of these inhibitors to potentiate CD47 immune checkpoint blockade therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
9. The ATDC (TRIM29) Protein Binds p53 and Antagonizes p53-Mediated Functions.
- Author
-
Zhigang Yuan, Villagra, Alejandro, Lirong Peng, Coppola, Domenico, Glozak, Michele, Sotomayor, Eduardo M., Jiandong Chen, Lane, William S., and Seto, Edward
- Subjects
- *
ATAXIA telangiectasia , *NUCLEIC acids , *P53 antioncogene , *CELL proliferation , *CANCER cells - Abstract
The ataxia telangiectasia group D-complementing (ATDC) gene product, also known as TRIM29, is a member of the tripartite motif (TRIM) protein family. ATDC has been proposed to form homo- or heterodimers and to bind nucleic acids. In cell cultures, ATDC expression leads to rapid growth and resistance to ionizing radiation (IR), whereas silencing of ATDC expression decreases growth rates and increases sensitivity to IR. Although ATDC is overexpressed in many human cancers, the biological significance of ATDC overexpression remains obscure. We report here that ATDC increases cell proliferation via inhibition of p53 nuclear activities. ATDC represses the expression of p53-regulated genes, including p21 and NOXA. Mechanistically, ATDC binds p53, and this interaction is potentially fine-tuned by posttranslational acetylation of lysine 116 on ATDC. The association of p53 and ATDC results in p53 sequestration outside of the nucleus. Together, these results provide novel mechanistic insights into the function of ATDC and offer an explanation for how ATDC promotes cancer cell proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
10. Erratum: The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance.
- Author
-
Villagra, Alejandro, Cheng, Fengdong, Wang, Hong-Wei, Suarez, Ildelfonso, Glozak, Michelle, Maurin, Michelle, Nguyen, Danny, Wright, Kenneth L, Atadja, Peter W, Bhalla, Kapil, Pinilla-Ibarz, Javier, Seto, Edward, and Sotomayor, Eduardo M
- Published
- 2009
- Full Text
- View/download PDF
11. Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers.
- Author
-
Gracia-Hernandez, Maria, Munoz, Zuleima, and Villagra, Alejandro
- Subjects
- *
DISEASE progression , *GENETIC mutation , *MELANOMA , *ONCOGENES , *IMMUNOMODULATORS , *CANCER patients , *HYDROLASES , *TUMOR suppressor genes , *EPIGENOMICS , *IMMUNOTHERAPY , *DRUG resistance in cancer cells , *CARRIER proteins , *CHEMICAL inhibitors - Abstract
Simple Summary: Melanoma affects over 300,000 people worldwide every year. Recent advancements in therapeutic treatments for melanoma patients, such as targeted therapies and immunotherapy, have improved the survival of patients without advanced disease. However, an important subset of patients remains refractory or develops resistance. Melanomagenesis, disease progression, and resistance to therapies are epigenetically regulated processes. Emerging preclinical and clinical research elucidates the mechanisms by which epigenetic drugs can prevent resistance or enhance the therapeutic efficacy of the aforementioned therapies in addition to chemotherapy, radiation therapy, and others. In this review, we assess the role of epigenetics in melanoma progression and resistance to targeted and immune therapies. Additionally, we discuss recent preclinical and clinical reports evaluating the use of epigenetic drugs as adjuvants to enhance the current therapeutic approaches for melanoma patients. Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma's susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
12. TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses
- Author
-
Vicente-Suarez, Ildelfonso, Brayer, Jason, Villagra, Alejandro, Cheng, Fengdong, and Sotomayor, Eduardo M.
- Subjects
- *
DENDRITIC cells , *CELL receptors , *CELL differentiation , *MESSENGER RNA , *T cells , *GENE expression , *ANTIGEN presenting cells , *IMMUNE response , *CD4 antigen - Abstract
Abstract: Dendritic cells (DCs) differentiated in the presence of IL-10 preferentially induce regulatory T-cells and tolerance. Whether the tolerogenic properties displayed by these DCs (Tol-DCs) can be overcome has not been fully explored. Here we show for the first time that Tol-DCs express higher levels of TLR5 mRNA, but not TLR4 or TLR9 mRNA relative to DCs differentiated with GM-CSF and IL-4 (BM-DCs). In response to flagellin, a natural TLR-5 ligand, Tol-DCs produced IL-12 but not IL-10. Unlike Tol-DCs stimulated with LPS, which produce high levels of IL-10 and fail to generate a cognate inflammatory response in CD4+ T-cells, flagellin-stimulated Tol-DCs promoted the differentiation of CD4+ T cells with a T-helper 1 phenotype. The divergent T-cell outcomes induced by Tol-DCs in response to different TLR-ligands highlights not only their plasticity, but also points to TLR5 ligation as a potential strategy to overcome tolerance in environments that are otherwise conducive to immune unresponsiveness. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
13. SWI/SNF-Independent Nuclease Hypersensitivity and an Increased Level of Histone Acetylation at the P1 Promoter Accompany Active Transcription of the Bone Master Gene Runx2.
- Author
-
Cruzat, Fernando, Henriquez, Berta, Villagra, Alejandro, Hepp, Matias, Lian, Jane B., Van Wijnen, Andre J., Stein, Janet L., Imbalzano, Anthony N., Stein, Gary S., and Montecino, Martin
- Subjects
- *
TRANSCRIPTION factors , *GENE expression , *CHROMATIN , *RNA polymerases , *ACETYLATION , *MESENCHYME - Abstract
The Runx2 transcription factor is essential for skeletal development as it regualtes expression of several key bone-related genes. Multiple lines of evidence indicate that expression of the Runx2/p57 isoform in osteoblasts is controlled by the distal P1 promoter. Alterations of chromatin structure are often associated with transcription and can be mediated by members of the SWI/SNF family of chromatin remodeling complexes, or by transcriptional coactivators that possess enzymatic activities that covalently modify structural components of the chromatin. Here, we report that a specific chromatin remodeling process at the proximal region (residues -400 to 35) of the Runx2 gene P1 promoter accompanies transcriptional activity in osteoblasts. This altered chromatin is reflected by the presence of two DNase I hypersensitive sites that span key regulatory elements for Runx2/p57 transcription. Chromatin remodeling and transcription of the Runx2 gene are associated with elevated levels of histone acetylation at the P1 promoter region and binding of active RNA polymerase II and are in independent of the activity of the SWI/SNF chromatin remodeling complex. Changes in chromatin organization at the P1 promoter are stimulated during differentiation of C2C12 mesenchymal cells to the osteoblastic lineage by treatment with BMP2. Together, our results a model in which changes in chromatin organization occur at very early stages of mesenchymal differentiation to facilitate subsequent expression of the Runx2/p57 isoform in oteoblastic cells. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
14. Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.
- Author
-
Moufarrij, Sara, Srivastava, Aneil, Gomez, Stephanie, Hadley, Melissa, Palmer, Erica, Austin, Paul Tran, Chisholm, Sarah, Diab, Noor, Roche, Kyle, Yu, Angela, Li, Jing, Zhu, Wenge, Lopez-Acevedo, Micael, Villagra, Alejandro, and Chiappinelli, Katherine B.
- Abstract
Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
15. Testing repeatability, measurement error and species differentiation when using geometric morphometrics on complex shapes: a case study of Patagonian lizards of the genus Liolaemus (Squamata: Liolaemini).
- Author
-
Vrdoljak, Juan, Sanchez, Kevin Imanol, Arreola-Ramos, Roberto, Huesa, Emilce Guadalupe Diaz, Villagra, Alejandro, Avila, Luciano Javier, and Morando, Mariana
- Subjects
- *
MEASUREMENT errors , *LIOLAEMUS , *MORPHOMETRICS , *SQUAMATA , *STATISTICAL reliability , *COLUBRIDAE - Abstract
The repeatability of findings is the key factor behind scientific reliability, and the failure to reproduce scientific findings has been termed the 'replication crisis'. Geometric morphometrics is an established tool in evolutionary biology. However, different operators (and/or different methods) could act as large sources of variation in the data obtained. Here, we investigated inter-operator error in geometric morphometric protocols on complex shapes of Liolaemus lizards, as well as measurement error in three taxa varying in their difficulty of digitalization. We also examined the potential for these protocols to discriminate among complex shapes in closely related species. We found a wide range of inter-operator error, contributing between 19.5% and 60% to the total variation. Moreover, measurement error increased with the complexity of the quantified shape. All protocols were able to discriminate between species, but the use of more landmarks did not imply better performance. We present evidence that complex shapes reduce repeatability, highlighting the need to explore different sources of variation that could lead to such low repeatability. Lastly, we suggest some recommendations to improve the repeatability and reliability of geometric morphometrics results. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
16. Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy.
- Author
-
Banik, Debarati, Moufarrij, Sara, and Villagra, Alejandro
- Subjects
- *
CANCER immunotherapy , *HISTONE deacetylase inhibitors , *NEURODEGENERATION , *DRUG efficacy , *CANCER invasiveness - Abstract
Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
17. T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model.
- Author
-
Woods, David M., Woan, Karrune V., Fengdong Cheng, Sodré, Andressa L., Dapeng Wang, Yongxia Wu, Zi Wang, Jie Chen, Powers, John, Pinilla-Ibarz, Javier, Yu Yu, Ya Zhang, Xuefeng Wu, Xiaoyan Zheng, Weber, Jeffrey, Hancock, Wayne W., Seto, Edward, Villagra, Alejandro, Xue-Zhong Yu, and Sotomayor, Eduardo M.
- Subjects
- *
MOUSE leukemia , *T cells , *HISTONE acetylation , *ENZYMES , *PHENOTYPES , *HISTONE deacetylase , *CYTOKINES , *CHROMATIN - Abstract
Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T cells resulted in its decreased expression. Experiments using HDAC11 knockout (KO) mice revealed that T cells from these mice displayed enhanced proliferation, proinflammatory cytokine production, and effector molecule expression. In addition, HDAC11KO T cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, over-expression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the Eomes and Tbet gene promoters in resting T cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T cells were refractory to tolerance induction.HDAC11KOT cells also mediated accelerated onset of acute graft-versus-host disease (GVHD) in a murine model, characterized by increased proliferation of T cells and expression of interferon-g, tumor necrosis factor, and EOMES. In addition, adoptive transfer of HDAC11KO T cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model. Taken together, these data demonstrate a previously unknown role of HDAC11 as a negative epigenetic regulator of T-cell effector phenotype and function. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
18. Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function.
- Author
-
Sahakian, Eva, Powers, John J., Chen, Jie, Deng, Susan L., Cheng, Fengdong, Distler, Allison, Woods, David M., Rock-Klotz, Jennifer, Sodre, Andressa L., Youn, Je-In, Woan, Karrune V., Villagra, Alejandro, Gabrilovich, Dmitry, Sotomayor, Eduardo M., and Pinilla-Ibarz, Javier
- Subjects
- *
HISTONE deacetylase , *EPIGENETICS , *SUPPRESSOR cells , *CELL populations , *ANTINEOPLASTIC agents , *CANCER immunotherapy - Abstract
Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo . MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
19. c-Abl Stabilizes HDAC2 Levels by Tyrosine Phosphorylation Repressing Neuronal Gene Expression in Alzheimer’s Disease.
- Author
-
Gonzalez-Zuñiga, Marcelo, Contreras, Pablo S., Estrada, Lisbell D., Chamorro, David, Villagra, Alejandro, Zanlungo, Silvana, Seto, Edward, and Alvarez, Alejandra R.
- Subjects
- *
TYROSINE , *PHOSPHORYLATION , *GENE expression , *ALZHEIMER'S disease , *GENETIC transcription , *POST-translational modification , *DRUG therapy , *IMATINIB - Abstract
Summary In Alzheimer’s disease (AD), there is a decrease in neuronal gene expression induced by HDAC2 increase; however, the mechanisms involved are not fully elucidated. Here, we described how the tyrosine kinase c-Abl increases HDAC2 levels, inducing transcriptional repression of synaptic genes. Our data demonstrate that (1) in neurons, c-Abl inhibition with Imatinib prevents the AβO-induced increase in HDAC2 levels; (2) c-Abl knockdown cells show a decrease in HDAC2 levels, while c-Abl overexpression increases them; (3) c-Abl inhibition reduces HDAC2-dependent repression activity and HDAC2 recruitment to the promoter of several synaptic genes, increasing their expression; (4) c-Abl induces tyrosine phosphorylation of HDAC2, a posttranslational modification, affecting both its stability and repression activity; and (5) treatment with Imatinib decreases HDAC2 levels in a transgenic mice model of AD. Our results support the participation of the c-Abl/HDAC2 signaling pathway in the epigenetic blockade of gene expression in AD pathology. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
20. A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs.
- Author
-
Fengdong Cheng, Lienlaf, Maritza, Hong-Wei Wang, Perez-Villarroel, Patricio, Lee, Calvin, Woan, Karrune, Rock-Klotz, Jennifer, Sahakian, Eva, Woods, David, Pinilla-Ibarz, Javier, Kalin, Jay, Jianguo Tao, Hancock, Wayne, Kozikowski, Alan, Seto, Edward, Villagra, Alejandro, and Sotomayor, Eduardo M.
- Subjects
- *
T cells , *HISTONE deacetylase , *GENETIC regulation of enzymes , *NUCLEOTIDE sequence , *CYTOPLASMIC inheritance - Abstract
APCs are critical in T cell activation and in the induction of T cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. In this study, to our knowledge we show for the first time that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells results in diminished production of the immunosuppressive cytokine IL-10 and induction of inflammatory APCs that effectively activate Ag-specific naive T cells and restore the responsiveness of anergic CD4+ T cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising amino acids 503-840 as being required for HDAC6 interaction with STAT3. Furthermore, by re-chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation--but no changes in STAT3 acetylation--as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance toward T cell immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
21. Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells.
- Author
-
Cheng, Fengdong, Lienlaf, Maritza, Perez-Villarroel, Patricio, Wang, Hong-Wei, Lee, Calvin, Woan, Karrune, Woods, David, Knox, Tessa, Bergman, Joel, Pinilla-Ibarz, Javier, Kozikowski, Alan, Seto, Edward, Sotomayor, Eduardo M., and Villagra, Alejandro
- Subjects
- *
HISTONE deacetylase regulation , *GENETIC regulation , *GENETIC transcription , *INTERLEUKIN-10 , *ANTIGEN presenting cells , *T cells - Abstract
Highlights: [•] HDAC6 interacts with HDAC11 in antigen presenting cells. [•] HDAC6 is a positive regulator of IL10 production. [•] Nuclear role of HDAC6 as transcriptional regulator. [•] HDACs as modulators of the APC plasticity to trigger T-cell activation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
22. Epigenetic Regulation of a Brain-specific Glycosyltransferase N-Acetylglucosaminyltransferase-IX (GnT-IX) by Specific Chromatin Modifiers.
- Author
-
Yasuhiko Kizuka, Shinobu Kitazume, Kyohei Okahara, Villagra, Alejandro, Sotomayor, Eduardo M., and Naoyuki Taniguchi
- Subjects
- *
GLYCOSYLTRANSFERASE genes , *GENE expression , *DNA , *CHROMATIN , *HISTONE deacetylase , *GLYCOSYLTRANSFERASES - Abstract
Expression of glycosyltransferase genes is essential for glycosylation. However, the detailed mechanisms of how glycosyltransferase gene expression is regulated in a specific tissue or during disease progression are poorly understood. In particular, epigenetic studies of glycosyltransferase genes are limited, although epigenetic mechanisms, such as histone and DNA modifications, are central to establish tissue-specific gene expression. We previously found that epigenetic histone activation is essential for brain-specific expression of N-acetylglucosaminyltransferase- IX (GnT-IX, also designated GnT-Vb), but the mechanism of brain-specific chromatin activation around GnT-IX gene (Mgat5b) has not been clarified. To reveal the mechanisms regulating the chromatin surrounding GnT-IX, we have investigated the epigenetic factors that are specifically involved with the mouse GnT-IX locus by comparing their involvement with other glycosyltransferase loci. We first found that a histone deacetylase (HDAC) inhibitor enhanced the expression of GnT-IX but not of other glycosyltransferases tested. By overexpression and knockdown of a series of HDACs, we found that HDAC11 silenced GnT-IX. We also identified the O-GlcNAc transferase (OGT) and ten-eleven translocation-3 (TET3) complex as a specific chromatin activator of GnT-IX gene. Moreover, chromatin immunoprecipitation (ChIP) analysis in combination with OGT or TET3 knockdown showed that this OGT-TET3 complex facilitates the binding of a potent transactivator, NeuroD1, to the GnT-IX promoter, suggesting that epigenetic chromatin activation by the OGT-TET3 complex is a prerequisite for the efficient binding of NeuroD1. These results reveal a new epigenetic mechanism of brainspecific GnT-IX expression regulated by defined chromatin modifiers, providing new insights into the tissue-specific expression of glycosyltransferases. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
23. Author Correction: Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.
- Author
-
Moufarrij, Sara, Srivastava, Aneil, Gomez, Stephanie, Hadley, Melissa, Palmer, Erica, Austin, Paul Tran, Chisholm, Sarah, Diab, Noor, Roche, Kyle, Yu, Angela, Li, Jing, Zhu, Wenge, Lopez-Acevedo, Micael, Villagra, Alejandro, and Chiappinelli, Katherine B.
- Subjects
- *
OVARIAN cancer , *OVARIAN tumors - Published
- 2021
- Full Text
- View/download PDF
24. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.
- Author
-
Youn, Je-In, Kumar, Vinit, Collazo, Michelle, Nefedova, Yulia, Condamine, Thomas, Cheng, Pingyan, Villagra, Alejandro, Antonia, Scott, McCaffrey, Judith C, Fishman, Mayer, Sarnaik, Amod, Horna, Pedro, Sotomayor, Eduardo, and Gabrilovich, Dmitry I
- Subjects
- *
EPIGENETICS , *GENE silencing , *RETINOBLASTOMA , *GENETIC regulation , *CANCER cell differentiation , *SUPPRESSOR cells , *MONOCYTES , *IMMUNOREGULATION - Abstract
Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6ChiLy6G− inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
25. Selective Histone Deacetylase6 Inhibitors BearingSubstituted Urea Linkers Inhibit Melanoma Cell Growth.
- Author
-
Bergman, Joel A., Woan, Karrune, Perez-Villarroel, Patricio, Villagra, Alejandro, Sotomayor, Eduardo M., and Kozikowski, Alan P.
- Subjects
- *
MELANOMA treatment , *HISTONE deacetylase inhibitors , *CANCER cell growth , *UREA , *AROMATIC compounds , *INHIBITION of cellular proliferation - Abstract
The incidence of malignant melanoma has dramaticallyincreasedin recent years thus requiring the need for improved therapeutic strategies.In our efforts to design selective histone deactylase inhibitors (HDACI),we discovered that the aryl urea 1is a modestly potentyet nonselective inhibitor. Structure–activity relationshipstudies revealed that adding substituents to the nitrogen atom ofthe urea so as to generate compounds bearing a branched linker groupresults in increased potency and selectivity for HDAC6. Compound 5gshows low nanomolar inhibitory potency against HDAC6 anda selectivity of ∼600-fold relative to the inhibition of HDAC1.These HDACIs were evaluated for their ability to inhibit the growthof B16 melanoma cells with the most potent and selective HDAC6I beingfound to decrease tumor cell growth. To the best of our knowledge,this work constitutes the first report of HDAC6-selective inhibitorsthat possess antiproliferative effects against melanoma cells. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
26. Stat3 Inhibition Augments the Immunogenicity of B-cell Lymphoma Cells, Leading to Effective Antitumor Immunity.
- Author
-
Fengdong Cheng, Hongwei Wang, Horna, Pedro, Zi Wang, Bijal Shah, Sahakian, Eva, Woan, Karrune V., Villagra, Alejandro, Pinilla-Ibarz, Javier, Sebti, Said, Smith, Mitchell, Jianguo Tao, and Sotomayor, Eduardo M.
- Subjects
- *
B cell lymphoma , *LYMPHOMA treatment , *CANCER chemotherapy , *IMMUNE system , *ANTINEOPLASTIC agents , *TUMOR treatment - Abstract
Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non--Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4+ T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
27. Modulation of antigen-presenting cells by HDAC inhibitors: implications in autoimmunity and cancer.
- Author
-
Woan, Karrune V, Sahakian, Eva, Sotomayor, Eduardo M, Seto, Edward, and Villagra, Alejandro
- Subjects
- *
CANCER treatment , *IMMUNOREGULATION , *CELLULAR immunity , *CYTOKINES , *CANCER cells , *CELL adhesion molecules - Abstract
There is a growing body of evidence to support the use of histone deacetylase inhibitors (HDACi) in the treatment of diverse conditions from autoimmunity to cancer. In this context, HDACi have been ascribed many immunomodulatory effects, assigning novel and promising roles to these compounds. This review summarizes the current observations arising from both pre-clinical and clinical studies in these pathological conditions. However, it is left to be explained how a single agent can have both pro- and anti-inflammatory effects in either physiological or pathological conditions. This question is explored in greater detail by focusing on the effects of HDACi on antigen-presenting cells (APCs), key regulators of immune activation. In particular, HDACi modulation of molecules involved in antigen processing and presentation, as well as co-stimulatory and adhesion molecules, and cytokines will be discussed in the context of both professional and non-professional APCs. Professional APCs encompass classic immune cells; however, it is increasingly evident that other somatic cells, including cancer cells, are not immunologically inert and can display functions similar to professional APCs, a challenging feature that needs to be explored as a potential therapeutic target. In this way, professional and non-professional APCs can regulate their particular micro-environmental niche, affecting either a pro- or anti-inflammatory milieu. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
28. Histone Deacetylase Inhibitor LAQ824 Augments Inflammatory Responses in Macrophages through Transcriptional Regulation of IL-10.
- Author
-
Hongwei Wang, Fengdong Cheng, Woan, Karrune, Sahakian, Eva, Merino, Oscar, Rock-Klotz, Jennifer, Vicente-Suarez, Ildefonso, Pinilla-Ibarz, Javier, Wright, Kenneth L., Seto, Edward, Bhalla, Kapil, Villagra, Alejandro, and Sotomayor, Eduardo M.
- Subjects
- *
HISTONE deacetylase , *IMMUNOLOGY of inflammation , *MACROPHAGES , *T cells , *INTERLEUKIN-10 , *GENETIC repressors - Abstract
APCs are important in the initiation of productive Ag-specific T cell responses and the induction of T cell anergy. The inflammatory status of the APC at the time of encounter with Ag-specific T cells plays a central role in determining such divergent T cell outcomes. A better understanding of the regulation of proinflammatory and anti-inflammatory genes in its natural setting, the chromatin substrate, might provide novel insights to overcome anergic mechanisms mediated by APCs. In this study, we show for the first time, to our knowledge, that treatment of BALB/c murine macrophages with the histone deacetylase inhibitor LAQ824 induces chromatin changes at the level of the IL-10 gene promoter that lead to enhanced recruitment of the transcriptional repressors HDAC11 and PU.1. Such an effect is associated with diminished IL-10 production and induction of inflammatory cells able of priming naive Ag-specific T cells, but more importantly, capable of restoring the responsiveness of anergized Ag-specific CD4+ T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
29. Histone Deacetylase 8 Safeguards the Human Ever-Shorter Telomeres 1B (hEST1B) Protein from Ubiquitin-Mediated Degradation.
- Author
-
Lee, Heehyoung, Sengupta, Nilanjan, Villagra, Alejandro, Rezai-Zadeh, Natalie, and Seto, Edward
- Subjects
- *
HISTONES , *ENZYMES , *LYSINE , *BIOLOGY , *CELL division , *CARCINOGENESIS , *CANCER cells - Abstract
Histone deacetylases (HDACs) are enzymes that regulate the functions of histones as well as nonhistones by catalyzing the removal of acetyl groups from lysine residues. HDACs regulate many biological processes, including the cell division cycle and tumorigenesis. Although recent studies have implicated HDAC8 in tumor cell proliferation, the molecular mechanisms linking HDAC8 to cell growth remain unknown. Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. Importantly, HDAC8 regulation of hEST1B protein stability modulates total telomerase enzymatic activity. Our findings reveal a novel mechanism by which HDAC8 contributes to tumorigenesis by regulating telomerase activity. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
30. Bone-Specific Transcription Factor Runx2 Interacts with the 1α,25-Dihydroxyvitamin D3 Receptor To Up-Regulate Rat Osteocalcin Gene Expression in Osteoblastic Cells.
- Author
-
Paredes, Roberto, Arriagada, Gloria, Cruzat, Fernando, Villagra, Alejandro, Olate, Juan, Zaidi, Kaleem, Van Wijnen, Andre, Lian, Jane B., Stein, Gary S., Stein, Janet L., and Montecino, Martin
- Subjects
- *
TRANSCRIPTION factors , *BONES , *GENE expression , *VITAMIN D , *PROMOTERS (Genetics) , *CYTOLOGY , *MOLECULAR biology - Abstract
Bone-specific transcription of the osteocalcin (OC) gene is regulated principally by the Runx2 transcription factor and is further stimulated in response to 1α,25-dihydroxyvitamin D3 via its specific receptor (VDR). The rat OC gene promoter contains three recognition sites for Runx2 (sites A, B, and C). Mutation of sites A and B, which flank the 1α,25-dihydroxyvitamin D3-responsive element (VDRE), abolishes 1α,25-dihydroxyvitamin D3-dependent enhancement of OC transcription, indicating a tight functional relationship between the VDR and Runx2 factors. In contrast to most of the members of the nuclear receptor family, VDR possesses a very short N-terminal A/B domain, which has led to the suggestion that its N-terminal region does not contribute to transcriptional enhancement. Here, we have combined transient-overexpression, coimmunoprecipitation, in situ colocalization, chromatin immunoprecipitation, and glutathione S-transferase pull-down analyses to demonstrate that in osteoblastic cells expressing OC, VDR interacts directly with Runx2 bound to site B, which is located immediately adjacent to the VDRE. This interaction contributes significantly to 1α,25-dihydroxyvitamin D3-dependent enhancement of the OC promoter and requires a region located C terminal to the runt homology DNA binding domain of Runx2 and the N-terminal region of VDR. Together, our results indicate that Runx2 plays a key role in the 1α,25-dihydroxyvitamin D3-dependent stimulation of the OC promoter in osteoblastic cells by further stabilizing the interaction of the VDR with the VDRE. These studies demonstrate a novel mechanism for combinatorial control of bone tissue-specific gene expression. This mechanism involves the intersection of two major pathways: Runx2, a "master" transcriptional regulator of osteoblast differentiation, and 1α,25-dihydroxyvitamin D3, a hormone that promotes expression of genes associated with these terminally differentiated bone cells. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
31. Indocyanine Green-Nexturastat A-PLGA Nanoparticles Combine Photothermal and Epigenetic Therapy for Melanoma.
- Author
-
Ledezma, Debbie K., Balakrishnan, Preethi B., Cano-Mejia, Juliana, Sweeney, Elizabeth E., Hadley, Melissa, Bollard, Catherine M., Villagra, Alejandro, and Fernandes, Rohan
- Subjects
- *
DACARBAZINE , *EPIGENETICS , *MELANOMA , *MAJOR histocompatibility complex , *INDOCYANINE green , *NANOPARTICLES - Abstract
In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). We hypothesized that combining PTT with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. We utilized a nanoemulsion synthesis scheme to co-encapsulate ICG and NextA within stable and monodispersed INAPs. The INAPs exhibited concentration-dependent and near-infrared (NIR) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for PTT of melanoma cells in vitro. The INAPs functioned as effective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (HDAC) and HDAC6-specific activity in melanoma cells in vitro. When used for both PTT and epigenetic therapy in vitro, the INAPs increased the expression of co-stimulatory molecules and major histocompatibility complex (MHC) Class I in melanoma cells relative to controls. These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
32. Author Correction: Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells.
- Author
-
Knox, Tessa, Sahakian, Eva, Banik, Debarati, Hadley, Melissa, Palmer, Erica, Noonepalle, Satish, Kim, Jennifer, Powers, John, Gracia-Hernandez, Maria, Oliveira, Vasco, Cheng, Fengdong, Chen, Jie, Barinka, Cyril, Pinilla-Ibarz, Javier, Lee, Norman H., Kozikowski, Alan, and Villagra, Alejandro
- Subjects
- *
HISTONE deacetylase inhibitors , *MACROPHAGES , *CANCER cells - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
33. Epigenetic therapy for ovarian cancer: promise and progress.
- Author
-
Moufarrij, Sara, Dandapani, Monica, Arthofer, Elisa, Gomez, Stephanie, Srivastava, Aneil, Lopez-Acevedo, Micael, Villagra, Alejandro, and Chiappinelli, Katherine B.
- Subjects
- *
OVARIAN cancer , *GYNECOLOGIC cancer - Abstract
Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. Early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. Most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. While most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. New treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. Recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. Several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. In this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.