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Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines

Margaret E McLaughlin-Drubin1, Donglim Park, Karl Munger

  • 1Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|September 19, 2013
PubMed

Insights

The tumor suppressor p16(INK4A) inhibits cell proliferation by triggering senescence. Human papillomavirus (HPV) infection hijacks this pathway, creating a vulnerability to KDM6A/B inhibitors in cervical cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Virology

Background:

  • p16(INK4A) is a tumor suppressor inhibiting cyclin-dependent kinases 4 and 6 (CDK4/6).
  • Oncogenic stress and human papillomavirus (HPV) E7 oncoprotein induce p16(INK4A) expression, triggering cellular senescence.
  • Many tumors lose p16(INK4A) activity, but HPV-associated tumors paradoxically upregulate it.

Purpose of the Study:

  • To investigate the role of p16(INK4A) and KDM6B in HPV-associated cervical cancer.
  • To understand the mechanism of p16(INK4A) induction by HPV E7.
  • To identify potential therapeutic vulnerabilities in HPV-driven cancers.

Main Methods:

  • Analysis of p16(INK4A) expression in HPV-associated tumors.
  • Investigating the role of KDM6B in epigenetic regulation of p16(INK4A).
  • Assessing the impact of HPV E7 on cell survival and dependence on KDM6B.

Main Results:

  • HPV E7 induces p16(INK4A) expression via epigenetic derepression mediated by KDM6B.
  • HPV E7 expression creates an acute dependence on KDM6B for cell survival.
  • p16(INK4A) expression, critical for survival in this context, requires CDK4/CDK6 inhibition.

Conclusions:

  • HPV E7 exploits cellular senescence pathways, making HPV-driven cancer cells dependent on KDM6B.
  • In cervical cancer cells with inactivated retinoblastoma tumor suppressor, CDK4/CDK6 inhibition is essential for survival.
  • Small-molecule KDM6A/B inhibitors represent a potential therapeutic strategy for HPV-associated cancers.
Keywords:
apoptosisbiomarkercancer therapysynthetic lethality

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