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Co-regulation of senescence-associated genes by oncogenic homeobox proteins and polycomb repressive complexes

Nadine Martin1, Selina Raguz, Gopuraja Dharmalingam

  • 1Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, London, UK.

Cell Cycle (Georgetown, Tex.)
|September 27, 2013
PubMed

Insights

Homeobox proteins HLX1 and HOXA9 bypass cellular senescence by recruiting Polycomb repressive complexes (PRCs) to repress the p16(INK4a) gene. This mechanism, involving oncogenes and senescence, has implications for cancer development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Cellular senescence is a crucial tumor suppressor mechanism involving cell cycle arrest.
  • The p16(INK4a) gene is a key regulator of senescence, and its expression is silenced by Polycomb repressive complexes (PRCs).
  • The precise recruitment mechanisms of PRCs to target genes, including the INK4/ARF locus, are not fully understood.

Purpose of the Study:

  • To investigate the role of homeobox proteins HLX1 and HOXA9 in regulating cellular senescence.
  • To elucidate the mechanism by which HLX1 and HOXA9 influence PRC recruitment and gene repression.
  • To identify additional senescence-associated genes regulated by HLX1 and HOXA9.

Main Methods:

  • Investigated the interaction of HLX1 and HOXA9 with PRCs.
  • Analyzed the effect of HLX1 and HOXA9 on the INK4/ARF locus and p16(INK4a) expression.
  • Utilized gene expression analysis to identify additional PRC target genes regulated by HLX1 and HOXA9.

Main Results:

  • HLX1 and HOXA9 were found to recruit PRCs to repress p16(INK4a), thereby enabling bypass of cellular senescence.
  • Evidence was provided for the regulation of additional senescence-associated PRC target genes by HLX1 and HOXA9.
  • HLX1 and HOXA9 were confirmed as oncogenes implicated in leukemogenesis.

Conclusions:

  • HLX1 and HOXA9 play a significant role in senescence evasion through PRC-mediated repression of key senescence regulators.
  • The collaboration between homeobox proteins and PRCs represents a critical mechanism in both senescence regulation and cancer development.
  • Understanding this interplay offers potential therapeutic targets for cancer treatment.
Keywords:
HLX1HOXA9HomeoboxPolycombcancerp16INK4asenescence

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