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Oncogenic activity of Cdc6 through repression of the INK4/ARF locus

Susana Gonzalez1, Peter Klatt, Sonia Delgado

  • 1Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), E-28029 Madrid, Spain.

Nature
|March 31, 2006
PubMed

Insights

Overexpressed Cdc6 represses the INK4/ARF tumor suppressor locus by forming heterochromatin, promoting cancer development. This mechanism involves the RD(INK4/ARF) regulatory element and links Cdc6 to cellular immortalization and transformation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • The INK4/ARF locus, encoding crucial tumor suppressors (p15INK4b, ARF, p16INK4a), is frequently inactivated in human cancers.
  • Mechanisms regulating INK4/ARF locus expression remain largely unknown.

Purpose of the Study:

  • To investigate the regulatory mechanisms governing the INK4/ARF locus.
  • To explore the role of Cdc6 in the regulation of tumor suppressor gene expression.

Main Methods:

  • Identification of a DNA replication origin and a conserved noncoding element (RD(INK4/ARF)) at the INK4/ARF locus.
  • RNA-interference-mediated heterochromatinization of RD(INK4/ARF) to assess its regulatory function.
  • Analysis of Cdc6 expression levels and its correlation with INK4/ARF locus silencing and cancer phenotypes.

Main Results:

  • A multiprotein complex including Cdc6, Orc2, and MCMs assembles at the identified replication origin within the RD(INK4/ARF) element.
  • Heterochromatinization of RD(INK4/ARF) leads to transcriptional repression of the INK4/ARF locus.
  • High Cdc6 levels induce RD(INK4/ARF)-dependent repression, histone deacetylase recruitment, heterochromatin formation, and decreased expression of INK4/ARF tumor suppressors.
  • Cdc6 overexpression correlates with cellular immortalization, neoplastic transformation, and reduced p16INK4a levels in lung carcinomas.

Conclusions:

  • Aberrant Cdc6 expression oncogenically represses the INK4/ARF locus via the RD(INK4/ARF) element.
  • Cdc6 acts as a novel regulator of tumor suppressor gene expression through epigenetic mechanisms.
  • This pathway highlights a new mechanism by which Cdc6 contributes to cancer development.

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