Posttranscriptional Regulation of PER1 Underlies the Oncogenic Function of IREα

Cancer Res. 2013 Aug 1;73(15):4732-43. doi: 10.1158/0008-5472.CAN-12-3989. Epub 2013 Jun 10.

Abstract

Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-α substrate, thereby pointing toward an increased IRE1α activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • Unfolded Protein Response / physiology*
  • Xenograft Model Antitumor Assays

Substances

  • PER1 protein, human
  • Period Circadian Proteins
  • RNA, Messenger
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases