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Review
. 2016 Aug 2;7(31):50719-50734.
doi: 10.18632/oncotarget.9368.

SETD2: an epigenetic modifier with tumor suppressor functionality

Jun Li  1 , Gerben Duns  2 , Helga Westers  1 , Rolf Sijmons  1 , Anke van den Berg  3 , Klaas Kok  1
Affiliations
Review

SETD2: an epigenetic modifier with tumor suppressor functionality

Jun Li et al. Oncotarget. .

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.

Keywords: H3K36me3; SETD2; ccRCC; histone modification; tumor suppressor gene.

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Conflict of interest statement

There is no conflict of interest for any of the authors.

Figures

Figure 1
Figure 1. Schematic representation of SETD2-mediated trimethylation of H3K36 and an overview of the H3K36me3 readers that define its role in various biological processes
During the first round of transcription, the transcription elongation factor and histone chaperone SPT6-IWS1 are recruited to Ser2P CTD tail of RNA Pol II. This results in the recruitment of the SETD2-hnRNPL complex that trimethylates H3K36. This mark is preserved on the histones in the following rounds of transcription and serves as a signal beacon to recruit H3K36me3 readers (shown in grey boxes). Facilitates Chromatin Transcription (FACT) complex, Histone deacetylase (HDAC) complex, PU.1 (also known as Spi-1 proto-oncogene, SPI1)/ DNA (cytosine-5-)-methyltransferase (DNMTs) complex and Polycomb Repressive Complex 2 (PCR2) complex are recruited for chromatin structure remodeling to facilitate transcription elongation and to prevent cryptic transcription initiation. The spliceosome is recruited through MORF4L1 for splicing selection; PSIP1/CtIP complex is recruited through PSIP1 for homologous recombination (HR) repair of double strand breaks (DSBs) and hMutα complex is recruited through MSH6 for DNA mismatch repair.
Figure 2
Figure 2. Schematic representation of SETD2 with the location of functional domains and nonsynonymous mutations and variants
The location of nonsynonymous mutations was obtained from ExAC (Germline variants in ~120000 alleles; January 2016) and COSMIC (somatic variants in 23,249 cases; January 2016). Intronic regions and 3′- and 5′-untranslated regions are not shown. Red, position of inactivating variants; Blue, position of missense variants. For the COSMIC data, the height of the bar is relative to the number of mutations. For the ExAC data, the height of the bars indicate 1, 2-5, 6-10, or >10 variants per triplet.
Figure 3
Figure 3. Regulation of SETD2 expression
The long non-coding RNA HOTAIR regulates SETD2 expression at the transcriptional level by competitively blocking loading of CREB-P300-RNA Pol II complex to the SETD2 promoter. MicroRNA-106-5p (miR-106-5p) regulates SETD2 expression at the translational level by binding to the 3′-UTR of the SETD2 mRNA transcript.
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