POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation

Nat Commun. 2015 Oct 29;6:8704. doi: 10.1038/ncomms9704.

Abstract

Hyperactivation of the transcriptional factor E2F1 occurs frequently in human cancers and contributes to malignant progression. E2F1 activity is regulated by proteolysis mediated by the ubiquitin-proteasome system. However, the deubiquitylase that controls E2F1 ubiquitylation and stability remains undefined. Here we demonstrate that the deubiquitylase POH1 stabilizes E2F1 protein through binding to and deubiquitylating E2F1. Conditional knockout of Poh1 alleles results in reduced E2F1 expression in primary mouse liver cells. The POH1-mediated regulation of E2F1 expression strengthens E2F1-downstream prosurvival signals, including upregulation of Survivin and FOXM1 protein levels, and efficiently facilitates tumour growth of liver cancer cells in nude mice. Importantly, human hepatocellular carcinomas (HCCs) recapitulate POH1 regulation of E2F1 expression, as nuclear abundance of POH1 is increased in HCCs and correlates with E2F1 overexpression and tumour growth. Thus, our study suggests that the hyperactivated POH1-E2F1 regulation may contribute to the development of liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Proliferation*
  • E2F1 Transcription Factor / chemistry
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / physiopathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Protein Stability
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitination

Substances

  • E2F1 Transcription Factor
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • PSMD14 protein, human
  • PSMD14 protein, mouse
  • Trans-Activators
  • Ubiquitin
  • Proteasome Endopeptidase Complex

Associated data

  • GEO/GSE65210