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      Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers

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          Abstract

          Epigenetic regulation plays an important role in the occurrence, development and treatment of malignant tumors; and a great deal of attention has been paid to the histone methylation level in recent years. As a 230-kD epigenetic regulator, the histone H3 lysine 36 histone (H3K36) methyltransferase SETD2 is a key enzyme of the nuclear receptor SET domain-containing (NSD) family, which is associated with a specific hyperphosphorylated domain, a large subunit of RNA polymerase II (RNAPII), named RNAPII subunit B1 (RPB1), and SETD2 which methylates the ly-36 position of dimethylated histone H3 (H3K36me2) to generate trimethylated H3K36 (H3K36me3). SETD2 is involved in various cellular processes, including transcriptional regulation, DNA damage repair, non-histone protein-related functions and some other processes. Great efforts of high-throughput sequencing have revealed that SETD2 is mutated or its function is lost in a range of solid cancers, including renal cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, osteosarcoma, and so on. Mutation, or functional loss, of the SETD2 gene produces dysfunction in corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemotherapy resistance, and unfavorable prognosis, suggesting that SETD2 possibly acts as a tumor suppressor. However, its underlying mechanism remains largely unexplored. In the present study, we summarized the latest advances of effects of SETD2 expression at the mRNA and protein levels in solid cancers, and its potential molecular and cellular functions as well as clinical applications were also reviewed.

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          Most cited references 73

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

           J. Gao,  B. Aksoy,  U Dogrusoz (2013)
          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            Mechanisms and functions of DNA mismatch repair.

             Min Li (2007)
            DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSalpha and MutLalpha, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
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              Understanding the language of Lys36 methylation at histone H3.

              Histone side chains are post-translationally modified at multiple sites, including at Lys36 on histone H3 (H3K36). Several enzymes from yeast and humans, including the methyltransferases SET domain-containing 2 (Set2) and nuclear receptor SET domain-containing 1 (NSD1), respectively, alter the methylation status of H3K36, and significant progress has been made in understanding how they affect chromatin structure and function. Although H3K36 methylation is most commonly associated with the transcription of active euchromatin, it has also been implicated in diverse processes, including alternative splicing, dosage compensation and transcriptional repression, as well as DNA repair and recombination. Disrupted placement of methylated H3K36 within the chromatin landscape can lead to a range of human diseases, underscoring the importance of this modification.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2020
                5 March 2020
                : 11
                : 11
                : 3349-3356
                Affiliations
                Department of Oncology, the Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, No. 185 Juqian Road, Tianning District, Changzhou 213003, China.
                Author notes
                ✉ Corresponding authors: Xin Yang, Department of Oncology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, China, E-mail: yangxindoctor@ 123456163.com . Tel.: +8618861235566; Mei Ji, Department of Oncology, the Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou 213003, China, E-mail: zlkjimei@ 123456163.com , Tel.: +8613775181579.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav11p3349
                10.7150/jca.38391
                7097956
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                Categories
                Review

                Oncology & Radiotherapy

                setd2, mutation, tumor suppressor, solid cancers

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