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KRAS-driven miR-29b expression is required for tumor suppressor gene silencing
Shilpa Thakur1, Charles Brenner1
1Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Oncotarget
|November 2, 2017
Summary
KRAS activation silences tumor suppressor genes by reducing TET1. Inhibiting miR-29b restores TET1, reactivating tumor suppressor genes and offering a potential cancer treatment strategy.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Epigenetics
Background:
- KRAS activation promotes DNA methylation and silencing of tumor suppressor genes (TSGs).
- The ERK pathway, activated by KRAS, represses TET1 expression.
- TET1 normally maintains TSG promoters in an active, hydroxymethylated state.
Purpose of the Study:
- To identify molecules mediating KRAS-induced TET1 repression.
- To investigate the role of miR-29b in KRAS-driven TSG silencing.
- To explore therapeutic strategies targeting the KRAS-miR-29b-TET1 axis.
Main Methods:
- KRAS-transformed cell models.
- MicroRNA (miR-29b) inhibition assays.
- TET1 expression analysis.
- DNA methylation and hydroxymethylation studies.
- Lung cancer cell line gene expression data mining.
Main Results:
- miR-29b was identified as a KRAS-induced repressor of TET1.
- Ectopic miR-29b inhibition restored TET1 expression and TSG reactivation.
- KRAS signaling leads to miR-29b-dependent silencing of TET1 and TSG hypermethylation.
- Additional KRAS-suppressed TSGs were identified and reactivated by miR-29b inhibition and TET1 re-expression.
Conclusions:
- KRAS-driven oncogenesis involves miR-29b-mediated repression of TET1, leading to TSG silencing.
- miR-29b represents a potential circulating biomarker for KRAS-driven malignancies.
- Targeting miR-29b offers a rational therapeutic approach for specific cancers.
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