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

Michael G. Backlund, Jason R. Mann, Vijaykumar R. Holla, Qiong Shi, Takikoku Daikoku, Sudhansu K. Dey, Raymond N. DuBois

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Prostaglandin E2 (PGE2) promotes cancer progression by modulating proliferation, apoptosis, angiogenesis, and the immune response. Enzymatic degradation of PGE2 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 Snailmediated 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 PGE2 levels that contribute to progression of CRC.

Original languageEnglish (US)
Pages (from-to)9331-9337
Number of pages7
JournalCancer Research
Volume68
Issue number22
DOIs
StatePublished - Nov 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Backlund, M. G., Mann, J. R., Holla, V. R., Shi, Q., Daikoku, T., Dey, S. K., & DuBois, R. N. (2008). Repression of 15-hydroxyprostaglandin dehydrogenase involves histone deacetylase 2 and snail in colorectal cancer. Cancer Research, 68(22), 9331-9337. https://doi.org/10.1158/0008-5472.CAN-08-2893