MiR-410 is overexpressed in liver and colorectal tumors and enhances tumor cell growth by silencing FHL1 via a direct/indirect mechanism

PLoS One. 2014 Oct 1;9(10):e108708. doi: 10.1371/journal.pone.0108708. eCollection 2014.

Abstract

FHL1 is an important tumor-suppressor that is downregulated in multiple tumors by unknown mechanisms. We demonstrated that miR-410 specifically targets the 3'UTR of FHL1. Furthermore, using DNA bisulfite modification and sequencing experiments, we demonstrated that the FHL1 promoter is hypermethylated in cancer cells. FHL1 methylation is increased upon miR-410 expression, suggesting that the regulation of FHL1 by miR-410 occurs by a dual mechanism. Using chromatin immunoprecipitation assays, we observed that miR-410 overexpression results in the increased binding of DNMT3A at the FHL1 promoter, which could explain how miR-410 regulates FHL1 methylation. Importantly, in vitro and in vivo results suggest that miR-410 may have oncogenic properties. Furthermore, both miR-410 and DNMT3A are upregulated in clinical human liver and colorectal tumors cancers. Our results suggest that miR-410 may function as an oncomiR and are consistent with its key function in regulating FHL1 in certain digestive system cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • LIM Domain Proteins / genetics*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • MicroRNAs / genetics*
  • Muscle Proteins / genetics*
  • Promoter Regions, Genetic
  • Protein Binding

Substances

  • 3' Untranslated Regions
  • FHL1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • MIRN410 microRNA, human
  • MicroRNAs
  • Muscle Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A

Grant support

This work was supported by Postdoctoral Science Foundation (201150M1523) and National Natural Science Foundation (81301941 and 81272701). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.