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Drugs targeting SETDB1 in different types of cancer

Epigenetic regulation of gene expression has been ultimately linked to cancer development, with posttranslational histone modifications representing attractive targets for disease monitoring and therapy. Emerging data have demonstrated histone lysine (K) methylation by methyltransferase SETDB1 as a common denominator of gene regulation in several cancer types. SETDB1 reversibly catalyzes the di- and trimethylation of histone 3 (H3) K9 in euchromatic regions of chromosomes, inhibiting gene transcription within these regions and promoting a switch from euchromatic to heterochromatic states. Recent studies have implicated aberrant SETDB1 activity in the development of various types of cancers, including brain, head and neck, lung, breast, gastrointestinal, ovarian, endometrial and prostate cancer, mesothelioma, melanoma, leukemias, and osteosarcoma. Although its role has not been fully elucidated in every case, most data point toward a pro-oncogenic potential of SETDB1 via the downregulation of critical tumor-suppressive genes. Less commonly, however, SETDB1 can also acquire a tumor-suppressive role, depending on cancer type and stage. Here we provide an updated overview of the cellular and molecular effects underlying SETDB1 activity in cancer development and progression along with current targeting strategies in different cancer types, with promising effects either as a standalone therapy or in conjunction with other therapeutic agents.

Zinc fingers consist of one of the most abundant motifs in transcription factors and DNA-binding proteins. Recent studies provide evidence on the pathological implication of zinc finger proteins in various neurodevelopmental disorders and malignancies but their role in pediatric brain tumors is largely unexplored. To this end, we investigated the differential expression of zinc finger-containing genes along with relevant biological processes and pathways among four main brain tumor categories (pilocytic astrocytomas, ependymomas, medulloblastomas and glioblastomas). By employing an extended bioinformatic toolset, we performed a preliminary in silico study in order to identify the expression of zinc finger-containing genes and associated functions in pediatric brain tumors. Our data analysis reveals the prominent role of C2H2-type zinc finger-containing genes in the molecular mechanisms underlying pediatric brain tumors followed by the Ring and PHD finger types. Significant dysregulation of ABLIM2 and UHFR1 genes was detected in all tumor types drawing attention to the dysregulation of cell polarization process and Ubiquitin-Proteasome System (UPS) in the pathogenesis of pediatric brain tumors. Moreover, significant gene clustering was observed in multiple locations with two highly visible clusters revealing a contrast in gene regulation between medulloblastomas and the other three brain tumor types, indicating a promising area of future research.

Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01090-x.

Biobanks constitute an integral part of precision medicine. They provide a repository of biospecimens that may be used to elucidate the pathophysiology, support diagnoses, and guide the treatment of diseases. The pilot biobank of rare malignant neoplasms has been established in the context of the Hellenic Network of Precision Medicine on Cancer and aims to enhance future clinical and/or research studies in Greece by collecting, processing, and storing rare malignant neoplasm samples with associated data. The biobank currently comprises 553 samples; 384 samples of hematopoietic and lymphoid tissue malignancies, 72 samples of pediatric brain tumors and 97 samples of malignant skin neoplasms. In this article, sample collections and their individual significance in clinical research are described in detail along with computational methods developed specifically for this project. A concise review of the Greek biobanking landscape is also delineated, in addition to recommended technologies, methodologies and protocols that were integrated during the creation of the biobank. This project is expected to re‑enforce current clinical and research studies, introduce advances in clinical and genetic research and potentially aid in future targeted drug discovery. It is our belief that the future of medical research is entwined with accessible, effective, and ethical biobanking and that our project will facilitate research planning in the '‑omic' era by contributing high‑quality samples along with their associated data.

Epigenetic regulation of gene expression has been ultimately linked to cancer development, with posttranslational histone modifications representing attractive targets for disease monitoring and therapy. Emerging data have demonstrated histone lysine (K) methylation by methyltransferase SETDB1 as a common denominator of gene regulation in several cancer types. SETDB1 reversibly catalyzes the di- and trimethylation of histone 3 (H3) K9 in euchromatic regions of chromosomes, inhibiting gene transcription within these regions and promoting a switch from euchromatic to heterochromatic states. Recent studies have implicated aberrant SETDB1 activity in the development of various types of cancers, including brain, head and neck, lung, breast, gastrointestinal, ovarian, endometrial and prostate cancer, mesothelioma, melanoma, leukemias, and osteosarcoma. Although its role has not been fully elucidated in every case, most data point toward a pro-oncogenic potential of SETDB1 via the downregulation of critical tumor-suppressive genes. Less commonly, however, SETDB1 can also acquire a tumor-suppressive role, depending on cancer type and stage. Here we provide an updated overview of the cellular and molecular effects underlying SETDB1 activity in cancer development and progression along with current targeting strategies in different cancer types, with promising effects either as a standalone therapy or in conjunction with other therapeutic agents.

Brain tumors are regarded as the most prevalent solid neoplasms in children and the principal reason of death in this population. Even though surgical resection, radiotherapy and chemotherapy have improved outcome, a significant number of patients die in 6-12 months after diagnosis while those who survive, frequently experience side effects and relapses. Several studies suggest that many types of cancer including pediatric brain tumors are characterized by alterations in epigenetic profiles with deregulated chromatin remodeling and posttranslational covalent histone modifications playing a prominent role. Moreover, interplay of genetic and epigenetic changes has been associated to tumor growth and invasion as well as to modulation of patient's response to current treatment. Therefore, detection of tumor-specific histone changes and elucidation of the underlying gene defects will allow successful tailoring of personalized treatment. The goal of this review is to provide an update of genetic and epigenetic alterations that characterize pediatric brain tumors focusing on histone modifications, aiming at directing future molecular and epigenetic therapeutic targeting.

Paediatric gliomas represent the most common brain tumour in children. Early diagnosis and treatment greatly improve survival. Histological grade is the most significant classification system affecting treatment planning and prognosis. Paediatric gliomas depend on pathways and genes responsible for mitotic activity and cell proliferation as well as angiogenesis (MAPK, VEGF, EFGR pathways). Symptoms such as focal neurologic deficit or seizures can facilitate diagnosis, but they are not always present and therefore diagnosis is occasionally delayed. Imaging has adequate diagnostic accuracy (surpassing 90%), and novel imaging techniques such as MR spectroscopy and PET increase only slightly this percentage. Low grade gliomas (LGG) can be approached conservatively but most authors suggest surgical excision. High grade gliomas (HGG) are always operated with exception of specific contradictions including butterfly or extensive dominant hemisphere gliomas. Surgical excision is universally followed by radiotherapy and chemotherapy, which slightly increase survival. Inoperable cases can be managed with or without radiosurgery depending on location and size, with adjunctive use of radiotherapy and chemotherapy. Surgical excision must be aggressive and gross total resection (GTR) should be attempted, if possible, since it can triple survival. Radiosurgery is effective on smaller tumours of

BACKGROUND Pediatric brain tumors are characterized by altered epigenetic profiles and deregulated chromatin remodelling that affects gene expression. Histone lysine methylation has emerged as important chromatin function regulator, with potential role in glioma formation. Τhis study investigates the expression of histone lysine methyltransferases (SETDB1, SUV39H1, EZH2, MLL2, SETD2) and their corresponding methylation marks (H3K9me3, H3K27me3, H3K4me2/3, H3K36me3) in pediatric astrocytomas. MATERIAL AND METHODS Thirty-four (34) archival pediatric astrocytomas [27 low grade (I/II) and 7 high grade (III/IV) tumors; 21 males, 13 females; 1–15 years old] and 5 postmortem normal brain samples were studied. Methyltransferases expression and histone marks were detected by immunohistochemistry as H-score (intensity multiplied with cell percentage, 0–300) and validated by western blot. RESULTS Elevated nuclear SETD2 and SETDB1 staining was observed in all astrocytomas (median H-score:165 and 110, respectively). SETDB1 and SETD2 expression levels were positively associated (p=0.004), being higher in high grade compared to lower grade tumors (p=0.001, p=0.027, respectively). Furthermore, SETDB1 staining was significantly increased in male children (p=0.051) and negatively associated with patients age (p=0.028). A moderate nuclear and cytoplasmic staining was obtained for MLL2 at low grade (median H-score:84) compared to high grade tumors (median H-score:144). In accordance, lower SUV39H1 nuclear and cytoplasmic expression was detected in low grade tissues (median H score:85) compared to high grade (median H-score:160). EZH2 presented no significant nuclear expression. Increased nuclear staining of H3K9me3 and H4K20me3 repressive marks was observed in astrocytomas (median H-score:297 and 270, respectively), being positively associated (p=0.02). Elevated nuclear staining of H3K4me3 active mark (median H-score:210) was detected in astrocytomas, being significantly higher in high grade tumors (p=0.025) and in male children (p=0.036). CONCLUSION SETDB1, SETD2, SUV39H1 and MLL2 may play a significant role in modulating gene expression in pediatric astrocytomas. Increased presence of H3K9me3, H4K20me3 and H3K4me3 histone marks signifies their possible participation in gliomagenesis. Larger cohort studies need to elucidate the functional significance and underlying molecular mechanisms of these chromatin-modifying enzymes and respective histone changes in pediatric astrocytomas.