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Simple Summary: Epigenetic modification plays an important regulatory role in breast cancer progression. However, the relationship between epigenetic modification with tumor metabolism has not yet been fully elucidated. PDK1, as a key enzyme in glucose metabolism, mediates multiple tumors development. But, the mechanism of epigenetic modification in regulating PDK1 remains unclear in breast cancer. Here, we demonstrated that HDAC2 and EZH2 upregulated PDK1 expression through inhibiting miR-148a. Importantly, miR-148a targeting PDK1 regulated breast cancer cells glycolysis, invasion, epithelial-mesenchymal transition (EMT) and Adriamycin resistance. Our results suggested that the HDAC2/EZH2/miR-148a/PDK1 axis may be a promising potential therapeutic strategy. Background: Breast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated. Methods: Gene set enrichment analysis (GSEA) and Pearson's correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo. Results: We found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a—including miR-148a's ability to increase cell sensitivity to Adriamycin (ADR) treatment—inhibiting cell glycolysis, invasion and epithelial–mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression. Conclusion: Our study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future. [ABSTRACT FROM AUTHOR]

Background: Glucose metabolic reprogramming is a significant hallmark of malignant tumors including GBM. Previous studies suggest that microRNAs play key roles in modulating this process in GBM cells. miR-181b acts as a tumor suppressor miRNA in influencing glioma tumorigenesis. Our previous results showed that miR-181b was down-regulated in glioma cells and tissues. Methods: The extracellular acidification rate (ECAR), colony formation assay and levels of Glut1 and PKM2 were measured to assess the glucose metabolic and proliferation changes in GBM cells overexpressing miR-181b. Immunoblotting and luciferase reporter assay were performed to confirm the expression and role of SP1 as a direct target of miR-181b. ChIP assay was used to figure out the transcriptional regulation of SP1 on Glut1 and PKM2. In vivo study was examined for the role of miR-181b in GBM cells. Results: MiR-181b overexpression significantly reduced the glucose metabolic and colony formation ability of GBM cells. And, SP1 was confirmed as a direct target of miR-181b while upregulation of SP1 could reverse the influence of overexpression of miR-181b. Furthermore, Glut1 and PKM2 could be regulated by SP1. Finally, miR-181b could inhibit the tumor growth in vivo. Conclusions: Our article demonstrated the inhibitory effect of miR-181b on glucose metabolism and proliferation in GBM by suppressing SP1 expression. [ABSTRACT FROM AUTHOR]

Cancer-specific TERT promoter mutations have been linked to the reactivation of epigenetically silenced TERT gene by creating de novo binding motifs for E-Twenty-Six transcription factors, especially GABPA. How these mutations switch on TERT from epigenetically repressed states to expressed states have not been defined. Here, we revealed that EGFR activation induces ERK1/2-dependent phosphorylation of argininosuccinate lyase (ASL) at Ser417 (S417), leading to interactions between ASL and GABPA at the mutant regions of TERT promoters. The ASL-generated fumarate inhibits KDM5C, leading to enhanced trimethylation of histone H3 Lys4 (H3K4me3), which in turn promotes the recruitment of c-Myc to TERT promoters for TERT expression. Expression of ASL S417A, which abrogates its binding with GABPA, results in reduced TERT expression, inhibited telomerase activity, shortened telomere length, and impaired brain tumor growth in mice. This study reveals an unrecognized mechanistic insight into epigenetically activation of mutant TERT promoters where GABPA-interacted ASL plays an instrumental role. [Display omitted] • GABPA binds with S417-phosphorylated ASL and directs ASL to mutant TERT promoter • ASL-generated fumarate enhances H3K4me3 at mutant TERT promoter by inhibiting KDM5C • GABPA/ASL interaction is prerequisite for recruiting c-Myc to mutant TERT promoter • ASL S417 phosphorylation promotes TERT expression and GBM tumorigenesis Shi et al. report that through interacting with GABPA, S417-phosphorylated ASL locates on mutant regions of TERT promoters, where it generates fumarate to inhibit KDM5C and subsequently facilitates enrichment of H3K4me3 in these regions. This event promotes the recruitment of c-Myc for TERT transcription and GBM tumorigenesis. [ABSTRACT FROM AUTHOR]

Cr(VI) is broadly applied in industry. Cr(VI) exposure places a big burden on public health, thereby increasing the risk of lung squamous cell carcinoma (LUSC). The mechanisms underlying Cr(VI)‐induced LUSC remain largely elusive. Here, we report that the cancer stem cell (CSC)/tumour‐initiating cell (TIC)‐like subgroup within Cr(VI)‐transformed bronchial epithelial cells (CrT) promotes lung cancer tumourigenesis. Mechanistically, Cr(VI) exposure specifically increases the expression levels of aldehyde dehydrogenase 1A1 (ALDH1A1), a CSC marker, through KLF4‐mediated transcription. ALDH1A1 maintains self‐renewal of CrT/TICs and facilitates the expression and secretion of EGF from CrT/TICs, which subsequently promotes the activation of EGFR signalling in differentiated cancer cells and tumour growth of LUSC. In addition, the ALDH1A1 inhibitor A37 and gemcitabine synergistically suppress LUSC progression. Importantly, high ALDH1A1 expression levels are positively correlated with advanced clinical stages and predict poor survival in LUSC patients. These findings elucidate how ALDH1A1 modulates EGF secretion from TICs to facilitate LUSC tumourigenesis, highlighting new therapeutic strategies for malignant lung cancers. [ABSTRACT FROM AUTHOR]

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K M of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM , TFB1M , and TFB2M , resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis. • Hypoxia suppresses mitochondrial biogenesis of tumor cells • PGC-1α's activity is inhibited by K224 monomethylation under hypoxic conditions • KDM3A senses oxygen availability for its activity and demethylates PGC-1α • PGC-1α monomethylation reduces hypoxia-induced ROS and apoptosis for tumor growth Qian et al. demonstrated that KDM3A functions as an oxygen sensor and demethylates K224-monomethylated PGC-1α under normoxic conditions. Hypoxia inhibits KDM3A activity and increases PGC-1α K224 monomethylation, resulting in the inhibition of PGC-1α and PGC-1α-dependent mitochondrial biogenesis, a decrease of ROS levels and apoptosis, and the promotion of brain tumor development. [ABSTRACT FROM AUTHOR]

The PTEN tumor suppressor is frequently mutated or deleted in cancer and regulates glucose metabolism through the PI3K-AKT pathway. However, whether PTEN directly regulates glycolysis in tumor cells is unclear. We demonstrate here that PTEN directly interacts with phosphoglycerate kinase 1 (PGK1). PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. The protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated PGK1, thereby inhibiting glycolysis, ATP production, and brain tumor cell proliferation. In addition, knockin expression of a PGK1 Y324F mutant inhibits brain tumor formation. Analyses of human glioblastoma specimens reveals that PGK1 Y324 phosphorylation levels inversely correlate with PTEN expression status and are positively associated with poor prognosis in glioblastoma patients. This work highlights the instrumental role of PGK1 autophosphorylation in its activation and PTEN protein phosphatase activity in governing glycolysis and tumorigenesis. • PGK1, functioning as a protein kinase, autophosphorylates itself at Y324 • PGK1 autophosphorylation enhances its glycolytic activity via promoting ATP release • PTEN, functioning as a protein phosphatase, dephosphorylates PGK1 pY324 • PGK1 Y324 autophosphorylation promotes brain tumor formation Qian et al. demonstrate that PGK1 functions as a protein kinase and autophosphorylates itself at Y324, leading to subsequent PGK1 activation. This phosphorylation is dephosphorylated by the protein phosphatase activity of PTEN. Loss of PTEN expression in tumors enhances PGK1 activity, thereby promoting glycolysis and brain tumor growth. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence shows that long noncoding RNAs (lncRNAs) are important regulator molecules involved in diverse biological processes. Acquired drug resistance is a major challenge in the clinical treatment of glioblastoma (GBM), and lncRNAs have been shown to play a role in chemotherapy resistance. However, the underlying mechanisms by which lncRNA mediates TMZ resistance in GBM remain poorly characterized. Methods: Quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization assays were used to detect small nucleolar RNA host gene 12 (SNHG12) levels in TMZ-sensitive and TMZ-resistant GBM cells and tissues. The effects of SNHG12 on TMZ resistance were investigated through in vitro assays (western blots, colony formation assays, flow cytometry assays, and TUNEL assays). The mechanism mediating the high expression of SNHG12 in TMZ-resistant cells and its relationships with miR-129-5p, mitogen-activated protein kinase 1 (MAPK1), and E2F transcription factor 7 (E2F7) were determined by bioinformatic analysis, bisulfite amplicon sequencing, methylation-specific PCR, dual luciferase reporter assays, chromatin immunoprecipitation assays, RNA immunoprecipitation assays, immunofluorescence, qRT-PCR, and western blot. For in vivo experiments, an intracranial xenograft tumor mouse model was used to investigate SNHG12 function. Results: SNHG12 was upregulated in TMZ-resistant cells and tissues. Overexpression of SNHG12 led to the development of acquired TMZ resistance, while knockdown of SNHG12 restored TMZ sensitivity. An abnormally low level of DNA methylation was detected within the promoter region of SNHG12, and loss of DNA methylation made this region more accessible to the Sp1 transcription factor (SP1); this indicated that methylation and SP1 work together to regulate SNHG12 expression. In the cytoplasm, SNHG12 served as a sponge for miR-129-5p, leading to upregulation of MAPK1 and E2F7 and endowing the GBM cells with TMZ resistance. Disinhibition of MAPK1 regulated TMZ-induced cell apoptosis and the G1/S cell cycle transition by activating the MAPK/ERK pathway, while E2F7 dysregulation was primarily associated with G1/S cell cycle transition. Clinically, SNHG12 overexpression was associated with poor survival of GBM patients undergoing TMZ treatment. Conclusion: Our results suggest that SNHG12 could serve as a promising therapeutic target to surmount TMZ resistance, thereby improving the clinical efficacy of TMZ chemotherapy. [ABSTRACT FROM AUTHOR]

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy. [Display omitted] • Fumarate directly targets and succinates PTEN at C211 • C211 succination abrogates the interaction of PTEN with the cellular membrane • PTEN C211 succination is positively correlated with PI3K/AKT activation in PRCC2 • Inhibiting PTEN C211 succination or AKT sensitizes PRCC2 to sunitinib treatment Ge et al. report that fumarate, an oncometabolite, succinates PTEN at C211, which abrogates the binding of PTEN with the cellular membrane. C211 succination of PTEN thereby activates PI3K/AKT signaling and promotes tumor growth of PRCC2. Inhibiting PTEN C211 succination or AKT activation enhances sensitivity of PRCC2 to sunitinib treatment. [ABSTRACT FROM AUTHOR]

Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin −31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin −31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin −31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations. [ABSTRACT FROM AUTHOR]

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance. [ABSTRACT FROM AUTHOR]