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.
Highlights
Epigenetic gene regulation eventually leads to changes in gene function and phenotype without changes in DNA sequence [1]
The study confirmed that SET domain bifurcated 1 (SETDB1) is recruited by methyl-CpG DNA Binding Domain Protein 1 (MBD1) to the promoter region of p53BP2, and the co-occupation of DNA methyltransferase 3A (DNMT3A) and SETDB1 leads to a hypermethylated gene promoter [1]
The researchers discovered that SETDB1 occupies the promoter of inhibitor of DNA binding 2 (ID2) and methylates H3K9 to prevent ID2 binding to RNA polymerase II, through which it suppresses ID2 expression
Summary
Epigenetic gene regulation eventually leads to changes in gene function and phenotype without changes in DNA sequence [1]. Among epigenetic gene regulation mechanisms, histone methylation is extremely important and participates in gene expression and chromatin organization [2]. The process of histone methylation involves two enzyme systems, histone methyltransferases (HMTs) and histone demethylases (HDMs), the imbalance of which is closely related to tumourigenesis [3]. Histone lysine methyltransferases (HKMTs) are important epigenetic modificatory enzymes containing SET domains. Overexpression and downregulation of SETDB1 have been widely found in various cancers, but the detailed mechanisms are still unclear [2,11,12,13,14,15,16,17,18,19,20,21,22]. We summarize the biological functions of SETDB1 and its therapeutic relevance in lung cancer and mesothelioma, describing possible diagnostic and therapeutic prospects. Obesity and fatty liver Overexpression in lung cancer; Malignant tumours of the haematopoietic system and hepatocellular carcinoma Proliferation of lung cancer through ALK activation; Contribution to NSCLC cell growth
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