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 language | English (US) |
|---|---|
| Pages (from-to) | 2610-2618 |
| Number of pages | 9 |
| Journal | Genes and Development |
| Volume | 25 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2011 |
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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 journal › Article
}
TY - JOUR
T1 - Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2
AU - Zhang, Jing
AU - Kan, Shu
AU - Huang, Brian
AU - Hao, Zhenyue
AU - Mak, Tak W.
AU - Zhong, Qing
PY - 2011/12/15
Y1 - 2011/12/15
N2 - 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.
AB - 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.
KW - Apoptosis
KW - DNA damage
KW - HDAC2
KW - Mule
KW - P53
KW - Ubiquitination
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U2 - 10.1101/gad.170605.111
DO - 10.1101/gad.170605.111
M3 - Article
VL - 25
SP - 2610
EP - 2618
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 24
ER -