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Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and

Xudong Wu1,2,3, Ida Holst Bekker-Jensen2,3, Jesper Christensen2,3

  • 1Department of Cell Biology, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China.

Cell Research
|October 17, 2015
PubMed

Insights

Mutations in ASXL1 are linked to hematological tumors. This study reveals ASXL1-BAP1 complex deubiquitylation of Histone H2A is crucial for INK4B gene activation, suppressing tumor formation.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Biology

Background:

  • ASXL1 mutations are common in hematological tumors.
  • Loss of Asxl1 function promotes myeloid transformation in mice.
  • Polycomb group proteins regulate gene expression via Histone H2A ubiquitylation.

Purpose of the Study:

  • Investigate the role of ASXL1-BAP1 complex in Histone H2A deubiquitylation.
  • Determine the impact of ASXL1-dependent deubiquitylation on the INK4B-ARF-INK4A locus.
  • Elucidate the tumor suppressor function of ASXL1 in hematopoiesis.

Main Methods:

  • In vivo studies of ASXL1-BAP1 complex function.
  • Analysis of Histone H2A (H2AK119ub1) deubiquitylation.
  • Gene expression analysis of the INK4B-ARF-INK4A locus.
  • Assessment of ASXL1 depletion effects on cell proliferation and growth inhibition.

Main Results:

  • ASXL1-BAP1 complex mediates deubiquitylation of H2AK119ub1.
  • ASXL1 is essential for p15(INK4B) expression in response to oncogenic and anti-proliferative signals.
  • ASXL1 mutations correlate with reduced p15(INK4B) levels and enhanced hematopoietic progenitor proliferation.
  • ASXL1 depletion confers resistance to growth inhibitory signals.

Conclusions:

  • ASXL1/BAP1-mediated H2A deubiquitylation is critical for INK4B locus activation.
  • ASXL1 acts as a tumor suppressor by regulating INK4B expression through epigenetic mechanisms.
  • Dysregulation of ASXL1-dependent deubiquitylation contributes to tumorigenesis in hematological malignancies.

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