Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers

Abstract

Epigenetic regulation plays an important role in the occurrence, development and treatment of malignant tumors; and a great deal of attention has been paid to the histone methylation level in recent years. As a 230-kD epigenetic regulator, the histone H3 lysine 36 histone (H3K36) methyltransferase SETD2 is a key enzyme of the nuclear receptor SET domain-containing (NSD) family, which is associated with a specific hyperphosphorylated domain, a large subunit of RNA polymerase II (RNAPII), named RNAPII subunit B1 (RPB1), and SETD2 which methylates the ly-36 position of dimethylated histone H3 (H3K36me2) to generate trimethylated H3K36 (H3K36me3). SETD2 is involved in various cellular processes, including transcriptional regulation, DNA damage repair, non-histone protein-related functions and some other processes. Great efforts of high-throughput sequencing have revealed that SETD2 is mutated or its function is lost in a range of solid cancers, including renal cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, osteosarcoma, and so on. Mutation, or functional loss, of the SETD2 gene produces dysfunction in corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemotherapy resistance, and unfavorable prognosis, suggesting that SETD2 possibly acts as a tumor suppressor. However, its underlying mechanism remains largely unexplored. In the present study, we summarized the latest advances of effects of SETD2 expression at the mRNA and protein levels in solid cancers, and its potential molecular and cellular functions as well as clinical applications were also reviewed.

Recent advances in upper gastrointestinal lymphomas: molecular updates and diagnostic implications

“…Mice with SETD2 loss showed expansion of γδ T cells, suggesting novel roles of the gene in T‐cell development and an early event in lymphomagenesis 158 . Inactivation of SETD2 has been demonstrated in many different tumour types, and seems to play a role in both disease initiation and disease progression 190 . Other genes mutated in MEITLs and related to epigenetics include the histone acetyltransferase gene CREBBP (26%) and EP300 , EZH2 , and ARID1 , which are frequently mutated in B‐cell lymphomas, whereas other genes that are frequently mutated in peripheral T‐cell lymphomas (PTCLs), such as TET2 , DNMT3A , and IDH1 / 2 , are usually wild‐type in MEITLs 159 …”

Osteosarcoma: A review with emphasis on pathogenesis and chemoresistance

“…CAIX inhibition in tumors in vivo resulted in enhanced cytotoxic response to paclitaxel. 145,146 Easwaran has suggested that the organization of the CSC epigenome in the tumor microenvironment, characterized by bivalence of promoter histone marks as discussed above, yields a highly poised configuration in which 161 Conversely, the histone methyltransferase NSD2, which imparts HeK36 dimethylation (H3K36me2), was shown to be upregulated in CDDP-resistant OS tumors. He and colleagues showed that NSD2 knockdown inhibited OS cell tumor formation in vivo and enhanced CDDP sensitivity.…”

<p>The Role of Methyltransferase NSD2 as a Potential Oncogene in Human Solid Tumors</p>

“…4 Tri-methyltransferase SETD2 is mutated in a range of human cancers and acts as a potential tumor suppressor. 5,6 NSD2, also known as MMSET (multiple myeloma SET domain) or WHSC1 (Wolf-Hirschhorn syndrome candidate 1), a member of the NSD protein family, [7][8][9] has been reported as the responsible gene for the disease of Wolf-Hirschhorn syndrome. It is also closely related to accelerated disease progression and rapid relapse in 15-20% of multiple myeloma (MM) harboring the t (4;14) chromosomal translocation.…”