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

Our plain-English summary of The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma, by L. Yuan, B. Sun, L. Xu, et al (International Journal of Molecular Sciences, 2021).

The study

• Authors: L. Yuan, B. Sun, L. Xu, L. Chen, W. Ou
• Journal: International Journal of Molecular Sciences
• Published: 2021;22(14)
• Type of article: Review
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article was a review, not a new study. The authors, at Zhejiang Sci-Tech University in China, summarized published research on SETDB1, an enzyme that adds chemical tags (methyl groups) to histone proteins and helps switch genes off, and on its possible relevance to lung cancer and mesothelioma. Asbestos appeared only as background: the authors wrote that asbestos fibre exposure and inhalation is the most common cause of mesothelioma. No asbestos exposure was studied. In the studies reviewed, SETDB1 was generally amplified or overexpressed in lung cancer, and in non-small-cell lung cancer this was related to poorer overall survival and shorter disease-free survival. Some studies instead found lower SETDB1 in metastatic lung cancer. In mesothelioma, one cited study reported frequent inactivating SETDB1 mutations, with a mutation frequency of 10% (7 of 69 patients). Another reported a 6% SETDB1 mutation frequency among 110 patients. The authors concluded that SETDB1 may be a diagnostic marker and treatment target. They also said that its true function in mesothelioma remains unclear and that further studies, including animal experiments, are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published studies (no new data collected)
• Who was studied: Published laboratory, animal-embryo and tumour-genomics studies of SETDB1, focused on lung cancer and malignant pleural mesothelioma; no patients were studied by the authors themselves
• Exposure: No asbestos exposure was studied. The authors stated in background that asbestos fibre exposure and inhalation is the most common cause of mesothelioma; no fiber type is named. The subject of the review was the gene and enzyme SETDB1.
• Main results:
  • Across the reviewed studies, SETDB1 was overexpressed in lung cancer and inactivated in mesothelioma, which the authors took to indicate different roles in the two cancers
  • In non-small-cell lung cancer patients (reviewed studies), overexpression and amplification of SETDB1 were related to poor overall survival and shorter disease-free survival
  • In some reviewed lung cancer research, SETDB1 expression was markedly lower in highly metastatic sublines of the CL1 lung cancer cell line
  • A cited sequencing study of mesothelioma tissue from 216 patients found 2529 protein-altering somatic mutations, among which SETDB1 was significantly mutated
  • A cited study reported a 6% SETDB1 mutation frequency in 110 patients enrolled in ramucirumab studies (the article does not say these mutations were inactivating)
  • A cited study found frequent inactivating SETDB1 mutations in 78 primary mesothelioma tissues from 69 patients, a mutation frequency of 10% (7 of 69)
  • A cited study of germline mutations in 101 mesothelioma patients suggested that inherited missense variants in SETD2 and SETDB1 may be associated with predisposition to mesothelioma
  • In a cited study, four of five near-haploidization mesotheliomas with TP53 mutations also had point mutations or homozygous deletions of SETDB1
• The authors' conclusion: The authors concluded that SETDB1 may be a diagnostic biomarker and therapeutic target in lung cancer and mesothelioma. They stated that its true function in mesothelioma is still unknown and that further studies, including animal experiments, are needed before clinical use.
• Limitations the authors state:
  • The authors stated that the detailed mechanisms behind SETDB1 overexpression and downregulation in cancers are still unclear
  • The authors stated that no studies have yet shown a correlation between SETDB1 and the three most frequently mutated genes in mesothelioma (BAP1, NF2 and CDKN2A)

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, Chemotherapy, Biomarker.

Related studies

• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor — S.G. Gray, A.M. Baird, et al. (2012)
• Biological agents involved in malignant mesothelioma: relevance as biomarkers or therapeutic targets — S. Crispi, I. Cardillo, et al. (2010)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Loss of BAP1 function leads to EZH2-dependent transformation — L.M. LaFave, W. Béguelin, et al. (2015)
• Integrative Molecular Characterization of Malignant Pleural Mesothelioma — J. Hmeljak, F. Sanchez-Vega, et al. (2018)

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