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SETD2: an epigenetic modifier with tumor suppressor functionality
Jun Li1, Gerben Duns2, Helga Westers1
1Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
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.
Insights
Set domain containing 2 (SETD2) is a histone modifier implicated in cancer. Inactivating mutations in SETD2 are linked to tumor development, particularly in clear cell Renal Cell Cancer, offering new therapeutic targets.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Research
Background:
- Epigenetic regulatory machinery is crucial in understanding cancer.
- Genetic aberrations in epigenetic modifiers are linked to various cancers.
- Targeting the epigenome is a novel cancer treatment strategy.
Purpose of the Study:
- To review the structural characteristics and functions of Set domain containing 2 (SETD2).
- To explore the role of SETD2 in cancer development and its association with H3K36 trimethylation.
- To discuss the prevalence of SETD2 mutations in cancers and their potential contribution to tumorigenesis.
Main Methods:
- Literature review combining studies on SETD2 function across multiple species (yeast, Drosophila, C. elegans, mice, humans).
- Analysis of structural characteristics and functional roles of SETD2.
- Examination of SETD2's role as the primary human gene for H3K36 trimethylation (H3K36me3).
Main Results:
- SETD2 is the key enzyme responsible for H3K36 trimethylation.
- H3K36me3 modification is read by specific proteins that regulate transcription elongation, RNA processing, and DNA repair.
- SETD2-inactivating mutations are prevalent in various cancers, notably clear cell Renal Cell Cancer.
Conclusions:
- SETD2 mutations are associated with cancer development.
- Understanding SETD2 function and its inactivation is critical for developing targeted cancer therapies.
- SETD2-negative tumors represent a potential target for novel therapeutic strategies.
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