SETD2: an epigenetic modifier with tumor suppressor functionality.

Jun Li,Rolf Sijmons,Klaas Kok,Gerben Duns,Helga Westers,Anke Van Den Berg

doi:10.18632/oncotarget.9368

Jun Li, Rolf Sijmons + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.9368

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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.

Highlights

In recent years, Set domain containing 2 (SETD2) has attracted a lot of interest as a gene whose inactivation is involved in tumor initiation and progression
Faber et al [1] had already identified a protein encoded by SETD2 in 1998 using a two-hybrid-based approach to search for proteins that interact with Huntingtin, the protein known to be associated with Huntington’s disease (HD)
In the final part of the review, we focus on how loss of SETD2 function can contribute to cancer development

Summary

Introduction

SETD2 has attracted a lot of interest as a gene whose inactivation is involved in tumor initiation and progression. PTBP1 is recruited by histone tail-binding protein Mortality Factor 4 like 1 (MORF4L1, known www.impactjournals.com/oncotarget as Eaf3 and MRG15), which recognizes H3K36me3 through its chromo domain [39, 50]. The enriched level of H3K36me3 in transcribed regions serves to restore chromatin structure after transcription and functions in maintaining genomic integrity.

Results

Conclusion