Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion

Nat Genet. 2013 Jul;45(7):739-746. doi: 10.1038/ng.2654. Epub 2013 Jun 2.

Abstract

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cellular Senescence / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Down-Regulation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Genes, Tumor Suppressor* / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Neoplasm Invasiveness
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • SOX9 Transcription Factor / genetics*
  • SOX9 Transcription Factor / metabolism
  • SOX9 Transcription Factor / physiology
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • DNA-Binding Proteins
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Transcription Factors
  • ZBTB7A protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human

Associated data

  • GEO/GSE46473