Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer

By D. Lodygin, V. Tarasov, A. Epanchintsev, C. Berking, T. Knyazeva, H. Körner, P. Knyazev, J. Diebold, H. Hermeking. Cell Cycle, 2008

806 citations recorded by the source corpus.

Recently, we and others identified the microRNA miR-34a as a target of the tumor suppressor gene product p53. Ectopic miR-34a induces a G1 cell cycle arrest, senescence and apoptosis. Here we report that miR-34a expression is silenced in several types of cancer due to aberrant CpG methylation of its promoter. 19 out of 24 (79.1%) primary prostate carcinomas displayed CpG methylation of the miR-34a promoter and concomitant loss of miR-34a expression. CpG methylation of the miR-34a promoter was also detected in breast (6/24; 25%), lung (7/24; 29.1%), colon (3/23; 13%), kidney (3/14; 21.4%), bladder (1/5; 20%) and pancreatic (3/19; 15.7%) carcinoma lines, as well as in melanoma cell lines (19/44; 43.2%) and primary melanoma (20/32; 62.5%). Silencing of miR-34a was dominant over its transactivation by p53/DNA damage. Re-expression of miR-34a in prostate and pancreas carcinoma cell lines induced senescence and cell cycle arrest at least in part by targeting CDK6. These results show that miR-34a represents a tumor suppressor gene which is inactivated by CpG methylation and subsequent transcriptional silencing in a broad range of tumors.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8730cb72b4229b1316bcac36f63d90bd039f6698

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Citations in the corpus

MicroRNA function in cancer: oncogene or a tumor suppressor? (2009, background): “MiR-34a expression is silenced in several types of cancer due to aberrant CpG methylation of its promoter [44].”
miR-34 – a microRNA replacement therapy is headed to the clinic (2012, background): “…cancers of the lung (Bommer et al., 2007; Lodygin et al., 2008; Gallardo et al., 2009; Wiggins et al., 2010), prostate (Fujita et al., 2008; Lodygin et al., 2008), breast (Lodygin et al., 2008; Vogt et al., 2011), pancreas (Chang et al., 2007; Lodygin et al., 2008; Vogt et al., 2011),…”
microRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes (2009, neutral): “It was also recently shown that miR-34a was inactivated by aberrant CpG methylation in multiple types of cancer, but brain tumors were not investigated (32).”
miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions (2011, background): “Interestingly, the miR‐34a and miR‐34b/c genes are silenced by CpG methylation in numerous types of tumors, among them colorectal cancer, and may therefore represent tumor suppressor genes.(12,13) A number of mRNAs have been shown to be direct miR‐34a/b/c targets,(11) which encode factors required f”
Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34 (2010, background): “In addition, frequent hypermethylation of the miR-34a promoter is another mechanism that can lead to reduced miR-34a expression in lung cancer and other cancer types (7, 11).”
MicroRNAs in development and disease. (2011, background): “Another gene that is silenced in CRC tumors and cell lines by GpC hypermethylation is miR-34a/b/c (380, 617).”