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

Jing Zhang, Shu Kan, Brian Huang, Zhenyue Hao, Tak W. Mak, Qing Zhong

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2610-2618
Number of pages9
JournalGenes and Development
Volume25
Issue number24
DOIs
StatePublished - Dec 15 2011

Fingerprint

Histone Deacetylases
Ubiquitin-Protein Ligases
Ubiquitination
Histone Deacetylase Inhibitors
DNA Damage
Null Lymphocytes
Apoptosis
Acetylation
Ligases
Ubiquitin
Epigenomics
Transcriptional Activation
Neoplasms
Fibroblasts
Growth

Keywords

  • Apoptosis
  • DNA damage
  • HDAC2
  • Mule
  • P53
  • Ubiquitination

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2. / Zhang, Jing; Kan, Shu; Huang, Brian; Hao, Zhenyue; Mak, Tak W.; Zhong, Qing.

In: Genes and Development, Vol. 25, No. 24, 15.12.2011, p. 2610-2618.

Research output: Contribution to journalArticle

Zhang, Jing ; Kan, Shu ; Huang, Brian ; Hao, Zhenyue ; Mak, Tak W. ; Zhong, Qing. / Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2. In: Genes and Development. 2011 ; Vol. 25, No. 24. pp. 2610-2618.
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