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

Genes & development | Dec 15, 2011

Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. Administration of HDAC inhibitors (HDACis) leads to growth inhibition, differentiation, and apoptosis of cancer cells. Understanding the regulatory mechanism of HDACs is imperative to harness the therapeutic potentials of HDACis. Here we show that HDACi- and DNA damage-induced apoptosis are severely compromised in mouse embryonic fibroblasts lacking a HECT domain ubiquitin ligase, Mule (Mcl-1 ubiquitin ligase E3). Mule specifically targets HDAC2 for ubiquitination and degradation. Accumulation of HDAC2 in Mule-deficient cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation, and apoptotic response upon DNA damage and Nutlin-3 treatments. These defects in Mule-null cells can be partially reversed by HDACis and fully rescued by lowering the elevated HDAC2 in Mule-null cells to the normal levels as in wild-type cells. Taken together, our results reveal a critical regulatory mechanism of HDAC2 by Mule and suggest this pathway determines the cellular response to HDACis and DNA damage.

Pubmed ID: 22016339 RIS Download

Mesh terms: Acetylation | Apoptosis | Cell Line, Tumor | DNA Damage | HEK293 Cells | Histone Deacetylase 2 | Histone Deacetylase Inhibitors | Humans | Protein Binding | Protein Stability | Tumor Suppressor Protein p53 | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA133228-03
  • Agency: NCI NIH HHS, Id: R01 CA133228
  • Agency: NCI NIH HHS, Id: R01 CA133228-02
  • Agency: NCI NIH HHS, Id: R01 CA133228-04
  • Agency: NCI NIH HHS, Id: R01 CA133228-01A1

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