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.
Highlights
KRAS mutations are among the most common alterations in human malignancies [1,2,3]
We previously showed that the ERK pathway induces transcriptional repression of TET1, which results in conversion of tumor suppressor genes (TSGs) promoters from a hydroxymethylated, active state to a hypermethylated and silenced state
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
Summary
KRAS mutations are among the most common alterations in human malignancies [1,2,3]. Because sporadic malignancies are heterogeneous, understanding the molecular differences among cancer subtypes is required to develop precision therapies. This is the central challenge of molecular oncology. Cellular transformation is a complex process involving activation of oncogenes and silencing of tumor suppressor genes (TSGs) [6]. Chromatin alterations are common hallmarks of cancer development and progression and are frequently linked to regulation of gene expression [7]. DNA methylation is among the best characterized epigenetic alteration linked to transcriptional silencing of TSGs in KRAS-mutated cancers [8,9,10]. Dysregulation of DNMT and TET function is widespread in cancer especially with respect to TSG silencing [13,14,15,16,17,18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
