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.
Backlund
Michael G
MG
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Mann
Jason R
JR
Holla
Vijaykumar R
VR
Shi
Qiong
Q
Daikoku
Takikoku
T
Dey
Sudhansu K
SK
DuBois
Raymond N
RN
D000818:Animals; D003110:Colonic Neoplasms / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases