KRAS-driven miR-29b expression is required for tumor suppressor gene silencing
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Shilpa Thakur1 and Charles Brenner1
1Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Charles Brenner, email: [email protected]
Keywords: DNA methylation, DNMT1, TET1, mir-29b, tumor suppressor gene
Received: May 07, 2017 Accepted: July 26, 2017 Published: August 19, 2017
KRAS activation drives DNA methylation and silencing of specific tumor suppressor genes (TSGs). We previously showed that the ERK pathway induces transcriptional repression of TET1, which results in conversion of TSG promoters from a hydroxymethylated, active state to a hypermethylated and silenced state. Here we identified miR-29b as a KRAS-induced molecule that represses TET1 expression. In KRAS-transformed cells, ectopic miR-29b inhibition restores expression of TET1, thereby reactivating TSGs by reducing methylation and restoring hydroxymethylation. Mining gene expression data of lung cancer cell lines identified additional TSGs suppressed by KRAS signaling whose expression was restored by inhibition of miR-29b and re-expression of TET1. Because KRAS changes TSG promoters from hydroxymethylated to hypermethylated with miR-29b-dependent silencing of TET1, we demonstrate a model in which DNMT1 is present on target promoters prior to KRAS transformation. In addition, we propose miR-29b as a potential circulating biomarker and target for rational treatment of specific malignancies.
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