Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

Abstract

SET domain-containing 2 (SETD2) is a lysine methyltransferase that catalyzes histone H3 lysine36 trimethylation (H3K36me3) and has been revealed to play important roles in the regulation of transcriptional elongation, RNA splicing, and DNA damage repair. SETD2 mutations have been documented in several cancers, including clear cell renal cell carcinoma (ccRCC). SETD2 deficiency is associated with cancer occurrence and progression by regulating autophagy flux, general metabolic activity, and replication fork speed. Therefore, SETD2 is considered a potential epigenetic therapeutic target and is the subject of ongoing research on cancer-related diagnosis and treatment. This review presents an overview of the molecular functions of SETD2 in H3K36me3 regulation and its relationship with ccRCC, providing a theoretical basis for subsequent antitumor therapy based on SETD2 or H3K36me3 targets.

Cancer metastasis under the magnifying glass of epigenetics and epitranscriptomics

“…Regarding SETD2, the HMT responsible of trimethylating H3K36, it is mutated in a range of tumor types, including 13% of cases in ccRCC [ 210 , 211 ]. Mechanistically, a study in ccRCC has described that the loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcriptional output through regulation of chromatin accessibility [ 132 ].…”

Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma

“…Along with PBRM1 and BAP1, the SETD2 gene is located in the 3p chromosome. It is a histone-lysine N-methyltransferase that plays a role in transcription regulation and alternative splicing [54]. Its loss-of-function mutation has been observed to cause microsatellite instability [55,56].…”

“…Interestingly, its mutation is frequently associated with PBRM1 mutation, but the association of the two mutations has no greater impact on overall prognosis than the single PBRM1 mutation [57]. Its mutation is reported with a frequency of 13-30% in different case series [54]. SETD2 loss of function is usually subclonal, meaning that it is only present in some cells within a single tumor [58].…”

Combination of PARP and DNA methylation inhibitors as a potential personalized therapy for SETD2-mutated clear-cell renal cancers

“…Notably, the combination of DAC with chemotherapeutic agents effectively demonstrates a synergistic impact in reducing the viability of renal cell carcinoma (RCC) cell lines ( 12 ). SETD2 is the leading histone methyltransferase, responsible for catalyzing the methylation of histone-3 at lysine-36 (H3K36me3), and according to a previous study, SETD2 deficiency can increase DNA double-strand breaks (DSB) damage by impairing homologous recombination (HR) ( 13 ). These observations have inspired Zhou and colleagues to examine the potential impacts of combination therapy with DNA hypomethylating agents (HMAs) and DNA repair inhibitors in ccRCC.…”