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Repression of 15-Hydroxyprostaglandin Dehydrogenase Involves Histone Deacetylase 2 and Snail in Colorectal Cancer

Departments of ¹ Medicine, ² Cell and Developmental Biology, and ³ Pediatrics, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee and ⁴ Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Raymond N. DuBois, Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Unit 118, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-4495; Fax: 713-745-1812; E-mail: rdubois{at}mdanderson.org.

Key Words: 15-Hydroxyprostaglandin dehydrogenase • prostaglandin E₂ • Snail • Histone deacetylase 2 • colorectal cancer

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 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 PGE₂ levels that contribute to progression of CRC. [Cancer Res 2008;68(22):9331–7]

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