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Inactivation of tumor suppressor genes: choice between genetic and epigenetic routes

Wen Yong Chen1, Stephen B Baylin

  • 1Cancer Biology Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.

Cell Cycle (Georgetown, Tex.)
|December 22, 2004
PubMed

Insights

Tumor suppressor gene inactivation can be epigenetic or genetic. A mouse model shows Hic1 disruption influences p53, affecting tumor development and revealing how inactivation mechanisms switch based on gene location.

Area of Science:

  • Oncology
  • Epigenetics
  • Genetics

Background:

  • Tumor suppressor gene inactivation is key in tumorigenesis, occurring through epigenetic or genetic mechanisms.
  • The reasons for choosing specific inactivation routes and the role of epigenetically silenced genes in cancer evolution remain unclear.

Purpose of the Study:

  • To investigate the influence of Hic1, a gene epigenetically silenced in human cancer, on the tumor suppressor gene p53.
  • To explore how the inactivation mechanism of Hic1 (epigenetic vs. genetic) impacts tumor development and virulence.
  • To analyze how gene knockout localization on chromosome 11 affects Hic1 inactivation pathways.

Main Methods:

  • Development and analysis of a mouse model with targeted disruption of the Hic1 gene.
  • Assessment of tumor incidence, spectrum, and virulence in relation to Hic1 and p53 gene status.
  • Investigation of the epigenetic and genetic inactivation mechanisms of Hic1 in tumor formation.

Main Results:

  • Disruption of Hic1 significantly influences p53's role in determining malignant tumor incidence, spectrum, and virulence.
  • The inactivation mechanism of Hic1 in tumors can shift from epigenetic to genetic.
  • This switch is dependent on the chromosomal localization of Hic1 and p53 knockouts on mouse chromosome 11.

Conclusions:

  • The study provides a valuable mouse model for understanding tumor suppressor gene inactivation.
  • Findings highlight the implications of epigenetic versus genetic loss of gene function in cancer development.
  • The interplay between Hic1 and p53, and the plasticity of inactivation mechanisms, offer insights into cancer evolution.

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