title: SETD2: an epigenetic modifier with tumor suppressor functionality.
abstract: In the past decade important progress has been made in our understanding of the epigenetic regulatory machinery. It has become clear that genetic aberrations in multiple epigenetic modifier proteins are associated with various types of cancer. Moreover, targeting the epigenome has emerged as a novel tool to treat cancer patients. Recently, the first drugs have been reported that specifically target SETD2-negative tumors. In this review we discuss the studies on the associated protein, Set domain containing 2 (SETD2), a histone modifier for which mutations have only recently been associated with cancer development. Our review starts with the structural characteristics of SETD2 and extends to its corresponding function by combining studies on SETD2 function in yeast, Drosophila, Caenorhabditis elegans, mice, and humans. SETD2 is now generally known as the single human gene responsible for trimethylation of lysine 36 of Histone H3 (H3K36). H3K36me3 readers that recruit protein complexes to carry out specific processes, including transcription elongation, RNA processing, and DNA repair, determine the impact of this histone modification. Finally, we describe the prevalence of SETD2-inactivating mutations in cancer, with the highest frequency in clear cell Renal Cell Cancer, and explore how SETD2-inactivation might contribute to tumor development.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Gerben
authors.initials: G
authors.lastname: Duns
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sijmons
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D002869:Chromosome Aberrations; D004331:Drosophila melanogaster; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D015398:Signal Transduction
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human
keywords: H3K36me3; SETD2; ccRCC; histone modification; tumor suppressor gene