Repression of 15-hydroxyprostaglandin dehydrogenase involves histone deacetylase 2 and snail in colorectal cancer.

Prostaglandin E(2) (PGE(2)) promotes cancer progression by modulating proliferation, apoptosis, angiogenesis, and the immune response. Enzymatic degradation of PGE(2) involves the NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Recent reports have shown a marked diminution of 15-PGDH expression in colorectal carcinomas (CRC). We report here that treatment of CRC cells with histone deacetylase (HDAC) inhibitors, including sodium butyrate and valproic acid, induces 15-PGDH expression. Additionally, we show that pretreatment of CRC cells with HDAC inhibitors can block epidermal growth factor-mediated or Snail-mediated transcriptional repression of 15-PGDH. We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. In vivo, we observe increased Hdac2 expression in Apc-deficient mouse adenomas, which inversely correlated with loss of 15-Pgdh expression. Finally, in human colon cancers, elevated HDAC expression correlated with down-regulation of 15-PGDH. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. These results also provide a cyclooxygenase-2-independent mechanism to explain increased PGE(2) levels that contribute to progression of CRC.

[1]  G. Chaudhuri,et al.  Human SLUG does not directly bind to CtBP1. , 2007, Biochemical and biophysical research communications.

[2]  H. Tai,et al.  Histone deacetylase inhibitors and transforming growth factor-β induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells , 2006 .

[3]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[4]  T. P. Pretlow,et al.  15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis , 2006, Proceedings of the National Academy of Sciences.

[5]  B. Karlan,et al.  15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. , 2006, Cancer research.

[6]  S. Dey,et al.  Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression. , 2006, Cancer research.

[7]  Andrew J. Wilson,et al.  Histone Deacetylase 3 (HDAC3) and Other Class I HDACs Regulate Colon Cell Maturation and p21 Expression and Are Deregulated in Human Colon Cancer* , 2006, Journal of Biological Chemistry.

[8]  K. Bomsztyk,et al.  Protocol for the fast chromatin immunoprecipitation (ChIP) method , 2006, Nature Protocols.

[9]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[10]  Joachim Diebold,et al.  Functional epigenomics identifies genes frequently silenced in prostate cancer. , 2005, Cancer research.

[11]  L. Sealy,et al.  Regulation of BRCA2 Gene Expression by the SLUG Repressor Protein in Human Breast Cells* , 2005, Journal of Biological Chemistry.

[12]  M. Salto‐Tellez,et al.  Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1 , 2005, Cell Death and Differentiation.

[13]  H. Tai,et al.  15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer* , 2005, Journal of Biological Chemistry.

[14]  H. Tai,et al.  NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. , 2004, Carcinogenesis.

[15]  J. Lutterbaugh,et al.  15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Dey,et al.  Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor δ , 2004 .

[17]  M. Salto‐Tellez,et al.  50 Inhibition of histone deacetylase 2 increases apoptosis and P21 expression , 2004 .

[18]  Ping Zhu,et al.  Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. , 2004, Cancer cell.

[19]  E. Ballestar,et al.  Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex , 2004, Molecular and Cellular Biology.

[20]  S. Dey,et al.  Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta. , 2004, Cancer cell.

[21]  J. Davie.  Inhibition of histone deacetylase activity by butyrate. , 2003, The Journal of nutrition.

[22]  T. Sugimura,et al.  Enhancement of colon carcinogenesis by prostaglandin E2 administration. , 2003, Carcinogenesis.

[23]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.

[24]  H. Tai,et al.  Prostaglandin catabolizing enzymes. , 2002, Prostaglandins & other lipid mediators.

[25]  L. Audoly,et al.  Metabolism of PGE2 by prostaglandin dehydrogenase is essential for remodeling the ductus arteriosus , 2002, Nature Medicine.

[26]  M. Zemel,et al.  Prostaglandin E2 Protects Intestinal Tumors from Nonsteroidal Anti-inflammatory Drug-induced Regression in ApcMin/+ Mice , 2002 .

[27]  M. Zemel,et al.  Prostaglandin E(2) protects intestinal tumors from nonsteroidal anti-inflammatory drug-induced regression in Apc(Min/+) mice. , 2002, Cancer research.

[28]  R. DuBois,et al.  Cyclooxygenase-2: a therapeutic target. , 2002, Annual review of medicine.

[29]  L. Marnett,et al.  COX-2: a target for colon cancer prevention. , 2002, Annual review of pharmacology and toxicology.

[30]  Rajnish A. Gupta,et al.  Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 , 2001, Nature Reviews Cancer.

[31]  H. Tai,et al.  Induction of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells. , 2000, Biochemical and biophysical research communications.

[32]  V. Steele,et al.  Enhancement of experimental colon cancer by genistein. , 1997, Cancer research.

[33]  F. Pichaud,et al.  Chromosomal localization of the type-I 15-PGDH gene to 4q34–q35 , 1997, Human Genetics.

[34]  R. Coffey,et al.  Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. , 1994, Gastroenterology.

[35]  B. Rigas,et al.  Altered eicosanoid levels in human colon cancer. , 1993, The Journal of laboratory and clinical medicine.