The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma

Abstract

SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase that exerts important effects on epigenetic gene regulation. SETDB1 complexes (SETDB1-KRAB-KAP1, SETDB1-DNMT3A, SETDB1-PML, SETDB1-ATF7IP-MBD1) play crucial roles in the processes of histone methylation, transcriptional suppression and chromatin remodelling. Therefore, aberrant trimethylation at H3K9 due to amplification, mutation or deletion of SETDB1 may lead to transcriptional repression of various tumour-suppressing genes and other related genes in cancer cells. Lung cancer is the most common type of cancer worldwide in which SETDB1 amplification and H3K9 hypermethylation have been indicated as potential tumourigenesis markers. In contrast, frequent inactivation mutations of SETDB1 have been revealed in mesothelioma, an asbestos-associated, locally aggressive, highly lethal, and notoriously chemotherapy-resistant cancer. Above all, the different statuses of SETDB1 indicate that it may have different biological functions and be a potential diagnostic biomarker and therapeutic target in lung cancer and mesothelioma.

Pancancer Analyses Reveal Genomics and Clinical Characteristics of the SETDB1 in Human Tumors

“…The epigenetic characters reflect the heterogeneity of tumors and indicate potential epigenetic changes, which lead to cancer cell invasion during tumor progress [ 46 , 47 ]. As an important player in tumor epigenetics, SETDB1 expression is significantly differential in most cancerous tissues and adjacent healthy tissues [ 8 , 48 – 51 ], which is consistent with our findings. It is demonstrated that SETDB1 is an oncogene and an important prognostic factor in some tumors.…”

SETDB1 as a cancer target: challenges and perspectives in drug design

“…These proteins have a variable I-SET insert, flanked by pre-and post-SET regions, and a common evolutionary conserved SET domain that is about 130 amino acid residues long and responsible for their catalytic activity. 4, [37][38][39][40] Sequence similarities found within SET domains and neighboring sequences, as well as other structural characteristics like the existence of additional clearly defined protein domains, are used to group SET-domain enzymes into a variety of families. The SUV39 family is the primary factor in the methylation of histone 3 lysine 9 (H3K9) in humans and has been most well described.…”

“…The KAP1 PHD domain enhances the binding of SETDB1 and serves as an intramolecular E3 ligase for sumoylation of the neighboring bromodomain. 37,56 The SETDB1/KAP1/KRAB-Zfp complex favors the creation of a microenvironment of heterochromatin at euchromatic sites together with all of the accompanying proteins, which helps mammalian cells silence some genes and exhibit position-effect variegation. 37,56 In addition to its effect on gene silencing, the SETDB1/ KAP1 complex has also been linked to genomic stability by preventing homologous recombination among the several zinc finger domains containing proteins (ZNFs).…”

“…37,56 The SETDB1/KAP1/KRAB-Zfp complex favors the creation of a microenvironment of heterochromatin at euchromatic sites together with all of the accompanying proteins, which helps mammalian cells silence some genes and exhibit position-effect variegation. 37,56 In addition to its effect on gene silencing, the SETDB1/ KAP1 complex has also been linked to genomic stability by preventing homologous recombination among the several zinc finger domains containing proteins (ZNFs). Despite the fact that the SETDB1/KAP1 complex is well known for playing a crucial part in the silencing of ERVs, ZNFs have evolved alongside waves of ERVs and are thought to be an adaptive defense against viral invasion.…”

“…Therefore, it is conceivable that the SETDB1/KAP1 complex served two roles during evolution, one being the suppression of ERV to ensure genomic stability and the other being the restriction of ZNF gene expansion to allow for a certain level of retrotransposon activity to bring new genomic diversity. 37 The interaction between the N-terminal domain of SETDB1 and the PHD domain of DNA methyltransferase 3A (DNMT3A) is another gene transcription suppression mechanism that has been extensively researched. Studies have shown that SETDB1 specifically interacts with DNMT3s but not DNA methyltransferase 1 (DNMT1) in vitro and in vivo.…”