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The tumor suppressor RASSF10 is upregulated upon contact inhibition and frequently epigenetically silenced in cancer

A M Richter1, S K Walesch, P Würl

  • 1Institute for Genetics, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany.

Oncogenesis
|April 5, 2013
PubMed

Insights

The Ras association domain family 10 (RASSF10) tumor suppressor is epigenetically silenced by promoter hypermethylation in lung, head and neck, sarcoma, and pancreatic cancers. RASSF10 reexpression suppresses cancer cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • The Ras association domain family (RASSF) includes tumor suppressors involved in apoptosis, cell cycle control, and microtubule stability.
  • Epigenetic inactivation is common in various cancers, affecting tumor suppressor gene function.
  • RASSF10 is a newly identified member of the RASSF family with potential tumor suppressor roles.

Purpose of the Study:

  • To investigate the epigenetic status and functional role of the putative tumor suppressor RASSF10 in cancer.
  • To determine the prevalence of RASSF10 promoter hypermethylation in different cancer types.
  • To explore the regulatory mechanisms and signaling pathways influencing RASSF10 expression.

Main Methods:

  • Analysis of RASSF10 promoter methylation in normal tissues, primary tumors, and cancer cell lines.
  • Treatment with 5-aza-2'-deoxycytidine to assess methylation reversal and gene reexpression.
  • Overexpression studies to evaluate RASSF10's effect on cancer cell colony formation.
  • Investigation of RASSF10 regulation by cell-cell contact, forskolin, protein kinase A (PKA), and Activator Protein 1 (AP-1) signaling.

Main Results:

  • RASSF10 promoter hypermethylation was identified in lung, head and neck (HN) cancer, sarcoma, and pancreatic cancer.
  • RASSF10 methylation levels increased from normal tissues to primary tumors and cancer cell lines.
  • 5-aza-2'-deoxycytidine treatment reversed methylation and restored RASSF10 expression.
  • RASSF10 overexpression suppressed colony formation in cancer cell lines.
  • RASSF10 expression is upregulated by cell-cell contact and regulated by PKA and AP-1 signaling via the cAMP pathway.
  • Knockdown of JunD, an AP-1 member, interfered with contact inhibition-induced RASSF10 expression.

Conclusions:

  • RASSF10 acts as a tumor suppressor epigenetically inactivated by promoter hypermethylation in multiple cancer types.
  • RASSF10 plays a role in contact inhibition and its expression is linked to the cAMP signaling pathway.
  • RASSF10 upregulation by PKA and JunD signaling upon contact inhibition suggests a novel tumor suppressive mechanism.

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