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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

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Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Hong Xu1, Jian Xian, Emmanuelle Vire

  • 1Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.

The Journal of Pathology
|July 22, 2014
PubMed

Insights

Loss of BRCA2 function in cancer cells leads to increased interferon-related gene expression. Interferons may offer new therapeutic strategies for BRCA2-mutated cancers.

Area of Science:

  • Genetics
  • Cancer Biology
  • Immunology

Background:

  • BRCA2 mutations are linked to early-onset breast cancer and DNA repair.
  • The tumor-suppressing role of BRCA2 is primarily associated with homologous recombination (HR) DNA repair.
  • Additional functions of BRCA2 beyond DNA repair are being investigated.

Purpose of the Study:

  • To identify novel functions of BRCA2.
  • To investigate the molecular consequences of BRCA2 loss in colorectal carcinoma cells.
  • To explore the relationship between BRCA2 deficiency and interferon-related gene expression.

Main Methods:

  • Generation of BRCA2-knockout HCT116 human colorectal carcinoma cells.
  • Genome-wide microarray analyses to identify gene expression changes.
  • Confirmation of gene expression in various BRCA2-deficient cell lines (human and mouse).
  • Analysis of interferon-stimulated response element (ISRE) activity.
  • Assessment of cell proliferation in the presence of interferons.

Main Results:

  • BRCA2 loss up-regulates a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G.
  • This up-regulation is independent of senescence and apoptosis and occurs in response to DNA damage or ionizing radiation.
  • BRCA2 directly represses IFN-related gene expression via the ISRE.
  • Interferon-beta (IFNβ) and Interferon-gamma (IFNγ) significantly reduce the colony-forming capacity of BRCA2-knockout cells.

Conclusions:

  • BRCA2 plays a role in repressing interferon-related gene expression.
  • Interferons show potential as therapeutic agents for cancers with BRCA2 mutations.
  • Further research into BRCA2's role in immune gene regulation is warranted.
Keywords:
BRCA2DNA damageinterferon

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