Histone deacetylase 3 (HDAC3) and other class IHDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer

被引:453
作者
Wilson, AJ
Byun, DS
Popova, N
Murray, LB
L'Italien, K
Sowa, Y
Arango, D
Velcich, A
Augenlicht, LH
Mariadason, JM
机构
[1] Montefiore Med Ctr, Albert Einstein Canc Ctr, Dept Oncol, Bronx, NY 10467 USA
[2] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Mol Targeting Canc Prevent, Kyoto 6028566, Japan
[3] Valle Hebron Hosp Res Inst, Program Funct Genom, Mol Biol & Biochem Res Ctr, Barcelona 08035, Spain
关键词
D O I
10.1074/jbc.M510023200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Inhibitors of histone deacetylases (HDACs) induce growth arrest, differentiation, and apoptosis of colon cancer cell lines in vitro and have demonstrated anti-cancer efficacy in clinical trials. Whereas a role for HDAC1 and -2 in mediating components of the HDAC inhibitor response has been reported, the role of HDAC3 is unknown. Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638(N/+) mice. HDAC3 was also maximally expressed in proliferating crypt cells in normal intestine. Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increasedapoptosis. SimilareffectswereobservedforHDAC2and, toa lesser extent, for HDAC1. HDAC3 silencing also selectively induced expression of alkaline phosphatase, amarker of colon cell maturation. Concurrent with its effect on cell growth, overexpression of HDAC3 and other Class I HDACs inhibited basal and butyrate-induced p21 transcription in a Sp1/Sp3-dependent manner, whereas silencing of HDAC3 stimulated p21 promoter activity and expression. However, the magnitude of the effects elicited by silencing of individual Class I HDACs was significantly less than that induced by HDAC inhibitors. These findings identify HDAC3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression. These findings also demonstrate that multiple Class I HDACs are involved in repressing p21 and suggest that the growthinhibitory and apoptotic effects induced byHDACinhibitors are probably mediated through the inhibition of multiple HDACs.
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页码:13548 / 13558
页数:11
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