Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

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Jing Zhang1, Shu Kan, Brian Huang

  • 1Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.

Genes & Development
|October 22, 2011
PubMed

Insights

Mule ubiquitin ligase targets HDAC2 for degradation, impacting cancer cell apoptosis. Mule deficiency compromises responses to DNA damage and HDAC inhibitors, revealing a key regulatory pathway.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Biology

Background:

  • Histone deacetylases (HDACs) are key epigenetic regulators implicated in human diseases, particularly cancers.
  • HDAC inhibitors (HDACis) show therapeutic promise by inducing cancer cell apoptosis and inhibiting growth.
  • Understanding HDAC regulation is crucial for optimizing HDACi-based cancer therapies.

Purpose of the Study:

  • To investigate the regulatory mechanism of HDAC2.
  • To elucidate the role of Mule (Mcl-1 ubiquitin ligase E3) in HDAC regulation.
  • To determine the impact of Mule deficiency on cellular responses to DNA damage and HDAC inhibitors.

Main Methods:

  • Utilized mouse embryonic fibroblasts deficient in Mule.
  • Assessed the effects of DNA damage and Nutlin-3 treatment on Mule-null cells.
  • Analyzed HDAC2 ubiquitination, degradation, p53 acetylation, and transcriptional activity.

Main Results:

  • Mule deficiency led to HDAC2 accumulation due to impaired ubiquitination and degradation.
  • Mule-null cells exhibited compromised p53 acetylation and activation, hindering apoptosis.
  • Cellular defects in Mule-null cells were partially reversed by HDACis and fully rescued by normalizing HDAC2 levels.

Conclusions:

  • Mule acts as a critical E3 ubiquitin ligase for HDAC2, targeting it for degradation.
  • The Mule-HDAC2 pathway is essential for effective p53-mediated apoptosis in response to DNA damage and HDAC inhibitors.
  • This pathway represents a potential therapeutic target for enhancing cancer treatment strategies.

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