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A hidden role of the inactivated FANCD2: upregulating ΔNp63

Jayabal Panneerselvam1, Anna Pickering, Jun Zhang

  • 1University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.

Oncotarget
|August 23, 2013
PubMed

Insights

Inactivated FANCD2, crucial for Fanconi Anemia (FA) pathway integrity, unexpectedly upregulates ΔNp63, promoting cancer cell proliferation and metastasis in non-FA tumors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • A compromised Fanconi Anemia (FA) pathway, particularly inactivated FANCD2, is linked to non-FA human tumors.
  • The precise mechanisms by which FA pathway impairment drives tumorigenesis remain largely unknown.

Purpose of the Study:

  • To investigate the molecular link between FA pathway dysfunction and cancer development.
  • To elucidate the role of FANCD2 inactivation in the upregulation of ΔNp63 and its contribution to tumorigenesis.

Main Methods:

  • Comparative analysis of ΔNp63 mRNA levels in cancer cells with intact versus impaired FA pathways.
  • Conditional manipulation of FANCD2 monoubiquitination/activation in 293T cells.
  • Identification of a DNA regulatory element mediating ΔNp63 upregulation by inactivated FANCD2.
  • Correlation analysis of FAVL and ΔNp63 expression in human cancer tissues.

Main Results:

  • Elevated ΔNp63 mRNA levels were observed in human cancer cells with impaired FA pathways and FANCD2 inactivation.
  • FANCD2 inactivation was confirmed to upregulate ΔNp63 in FA patient-derived fibroblasts.
  • A specific 189 bp DNA fragment downstream of the ΔNp63 P2 promoter was identified as mediating this upregulation.
  • Elevated ΔNp63 expression was sufficient to promote cancer cell proliferation and metastasis.
  • In vivo, FAVL, an inhibitor of FANCD2 activation, positively correlated with ΔNp63 expression in human cancers.

Conclusions:

  • Inactivated FANCD2 plays a novel role in upregulating ΔNp63, contributing to cancer pathogenesis.
  • This finding advances the understanding of how impaired FA pathway signaling contributes to human cancer development.
  • Targeting the FANCD2-ΔNp63 axis may offer new therapeutic strategies for cancers with FA pathway defects.

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