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 journalArticlepeer-review

    45 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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