Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer.
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 increased apoptosis. Similar effects were observed for HDAC2 and, to a lesser extent, for HDAC1. HDAC3 silencing also selectively induced expression of alkaline phosphatase, a marker 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 growth-inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.
Wilson
Andrew J
AJ
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Byun
Do-Sun
DS
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Popova
Natalia
N
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Murray
Lucas B
LB
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
L'Italien
Kaitlin
K
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Sowa
Yoshihiro
Y
Department of Molecular Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Arango
Diego
D
Program of Functional Genomics, Molecular Biology and Biochemistry Research Center (CIBBIM), Valle Hebron Hospital Research Institute, 08035 Barcelona, Spain.
Velcich
Anna
A
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Augenlicht
Leonard H
LH
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Mariadason
John M
JM
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467. Electronic address: jmariada@aecom.yu.edu.
D017209:Apoptosis; D018938:Caco-2 Cells; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology; D003110:Colonic Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D013997:Time Factors; D015854:Up-Regulation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases