Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2
Open Access
- 20 May 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 1 (5), e44
- https://doi.org/10.1038/cddis.2010.21
Abstract
Histone deacetylases (HDACs) are epigenetic regulators that are important for the control of various pathophysiological events. We found that HDAC inhibitors completely abolished transforming growth factor-β1 (TGF-β1)-induced apoptosis in AML-12 and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 or downregulation of HDAC1 by RNAi both suppressed TGF-β1-induced apoptosis. In addition, overexpression of HDAC1 enhanced TGF-β1-induced apoptosis, and the rescue of HDAC1 expression in HDAC1 RNAi cells restored the apoptotic response of cells to TGF-β1. These data indicate that HDAC1 functions as a proapoptotic factor in TGF-β1-induced apoptosis. In contrast, downregulation of HDAC2 by RNAi increased spontaneous apoptosis and markedly enhanced TGF-β1-induced apoptosis, suggesting that HDAC2 has a reciprocal role in controlling cell survival. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) by MEK1 inhibitor PD98059 or expression of a kinase-dead mutant of MEK1 restored the apoptotic response to TGF-β1 in HDAC1 RNAi cells. Strikingly, HDAC2 RNAi caused an inhibition of ERK1/2, and the spontaneous apoptosis can be abolished by reactivation of ERK1/2. Taken together, our data demonstrate that HDAC1 and 2 reciprocally affect cell viability by differential regulation of ERK1/2; these observations provide insight into the roles and potential mechanisms of HDAC1 and 2 in apoptosis.Keywords
This publication has 47 references indexed in Scilit:
- TGF-β1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinasesRespiratory Research, 2006
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancerNature Reviews Cancer, 2006
- Transforming growth factor β (TGF-β) and autoimmunityAutoimmunity Reviews, 2005
- Repression of Runx2 function by TGF-β through recruitment of class II histone deacetylases by Smad3The EMBO Journal, 2005
- Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1Cell Death & Differentiation, 2005
- Prostaglandin-dependent activation of ERK mediates cell proliferation induced by transforming growth factor β in mouse osteoblastic cellsBone, 2005
- Activation of the Erk Pathway Is Required for TGF-β1-Induced EMT In VitroNeoplasia, 2004
- Three proteins define a class of human histone deacetylases related to yeast Hda1pProceedings of the National Academy of Sciences of the United States of America, 1999
- Transforming Growth Factor β1 Rescues Serum Deprivation-induced Apoptosis via the Mitogen-activated Protein Kinase (MAPK) Pathway in MacrophagesPublished by Elsevier BV ,1999
- Histone Deacetylase Activity Is Required for Full Transcriptional Repression by mSin3ACell, 1997