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SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization

Ping Yi1, Weiya Xia, Ray-Chang Wu

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Genes & Development
|February 8, 2013
PubMed

Insights

Steroid receptor coactivator 3 (SRC-3) and TRAF4 promote cancer cell resistance to cytotoxic stress by inhibiting the tumor suppressor p53. This mechanism is linked to poor prognosis in breast cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Steroid receptor coactivator 3 (SRC-3) is an oncogenic coactivator implicated in drug resistance.
  • SRC-3's role in mediating resistance to cytotoxic stress in cancer is not fully understood.

Purpose of the Study:

  • To identify downstream genes of SRC-3 involved in cell resistance to cytotoxic stress.
  • To elucidate the molecular mechanism by which SRC-3 and its downstream targets confer resistance to cytotoxic agents.
  • To investigate the clinical significance of SRC-3 and TRAF4 in breast cancer prognosis.

Main Methods:

  • Lentiviral cDNA library rescue screening to identify SRC-3 downstream genes.
  • Analysis of gene expression correlation in human breast cancer tissues.
  • Cellular assays to assess resistance to stress-induced death and p53 protein levels.
  • Co-immunoprecipitation assays to determine protein-protein interactions between TRAF4, HAUSP, and p53.

Main Results:

  • TRAF4 was identified as a downstream gene of SRC-3 that confers resistance to cytotoxic stress.
  • TRAF4 expression is positively correlated with SRC-3 expression and inversely correlated with p53-regulated proapoptotic genes in breast cancers.
  • Overexpression of SRC-3 and TRAF4 inhibits the stabilization and activity of p53 in response to cytotoxic stress.
  • TRAF4 binds to HAUSP (USP7), blocking p53 deubiquitination and stabilization, thereby promoting cell survival.
  • TRAF4 overexpression is associated with poor prognosis in breast cancer patients.

Conclusions:

  • SRC-3 and its downstream effector TRAF4 promote resistance to cytotoxic stress by inhibiting p53.
  • The TRAF4-HAUSP-p53 axis represents a novel mechanism of drug resistance in breast cancer.
  • Targeting the SRC-3/TRAF4 pathway may offer therapeutic strategies for breast cancers, particularly those with intact p53.

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