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

Andrew J. Wilson, Do Sun Byun, Natalia Popova, Lucas B. Murray, Kaitlin L'Italien, Yoshihiro Sowa, Diego Arango, Anna Velcich, Leonard H. Augenlicht, John M. Mariadason

Research output: Contribution to journalArticle

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Abstract

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, 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 growth-inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.

Original languageEnglish (US)
Pages (from-to)13548-13558
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number19
DOIs
StatePublished - May 12 2006

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Histone Deacetylases
Colonic Neoplasms
Colon
Cells
Growth
Apoptosis
Cell Line
histone deacetylase 3
Butyrates
Cell growth
Transcription
Adenoma
Intestines
Alkaline Phosphatase
Tumors
Neoplasms
Cell Survival
Genes
Clinical Trials

ASJC Scopus subject areas

  • Biochemistry

Cite this

Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. / Wilson, Andrew J.; Byun, Do Sun; Popova, Natalia; Murray, Lucas B.; L'Italien, Kaitlin; Sowa, Yoshihiro; Arango, Diego; Velcich, Anna; Augenlicht, Leonard H.; Mariadason, John M.

In: Journal of Biological Chemistry, Vol. 281, No. 19, 12.05.2006, p. 13548-13558.

Research output: Contribution to journalArticle

Wilson, AJ, Byun, DS, Popova, N, Murray, LB, L'Italien, K, Sowa, Y, Arango, D, Velcich, A, Augenlicht, LH & Mariadason, JM 2006, 'Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer', Journal of Biological Chemistry, vol. 281, no. 19, pp. 13548-13558. https://doi.org/10.1074/jbc.M510023200
Wilson, Andrew J. ; Byun, Do Sun ; Popova, Natalia ; Murray, Lucas B. ; L'Italien, Kaitlin ; Sowa, Yoshihiro ; Arango, Diego ; Velcich, Anna ; Augenlicht, Leonard H. ; Mariadason, John M. / Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 19. pp. 13548-13558.
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AU - Murray, Lucas B.

AU - L'Italien, Kaitlin

AU - Sowa, Yoshihiro

AU - Arango, Diego

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