KRAS-driven miR-29b expression is required for tumor suppressor gene silencing

Shilpa Thakur; Charles Brenner

doi:10.18632/oncotarget.20364

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KRAS-driven miR-29b expression is required for tumor suppressor gene silencing

Journal article

Open access

Peer reviewed

KRAS-driven miR-29b expression is required for tumor suppressor gene silencing

Shilpa Thakur and Charles Brenner

Oncotarget, Vol.8(43), pp.74755-74766

2017

DOI: 10.18632/oncotarget.20364

PMCID: PMC5650376

PMID: 29088821

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Abstract

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.

DNA methylation

TET1

DNMT1

Research Paper

mir-29b

tumor suppressor gene

Details

Title: Subtitle: KRAS-driven miR-29b expression is required for tumor suppressor gene silencing
Creators: Shilpa Thakur - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Charles Brenner - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.8(43), pp.74755-74766
DOI: 10.18632/oncotarget.20364
PMID: 29088821
PMCID: PMC5650376
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: Impact Journals LLC
Language: English
Date published: 2017
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788599802771

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