HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis

Nat Commun. 2018 Jan 8;9(1):100. doi: 10.1038/s41467-017-02601-1.

Abstract

The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression. mir-615-3p is located in an intron of the HOXC5 gene, a member of the highly conserved homeobox family of transcription factors controlling embryogenesis and development. Unexpectedly, we found that HoxC5 also represses hTERT expression by disrupting the long-range interaction between hTERT promoter and its distal enhancer. The 3'UTR of hTERT and its upstream enhancer region are well conserved in long-lived primates. Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation. Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • 5' Untranslated Regions / genetics
  • Animals
  • Cell Differentiation / genetics*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Enhancer Elements, Genetic / genetics
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • MCF-7 Cells
  • Mice
  • MicroRNAs / genetics*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Promoter Regions, Genetic / genetics
  • Telomerase / biosynthesis*

Substances

  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • HOXC5 protein, human
  • Homeodomain Proteins
  • MIRN615 microRNA, human
  • MicroRNAs
  • TERT protein, human
  • Telomerase