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Homeodomain-Interacting Protein Kinase-2 Restrains Cytosolic Phospholipase A₂–Dependent Prostaglandin E₂ Generation in Human Colorectal Cancer Cells

Authors' Affiliations: Departments of ¹ Oncology and Neurosciences and ² Medicine, Centre of Excellence on Aging, University "G. d'Annunzio" and Center for the Study on Aging, "Gabriele D'Annunzio" University Foundation, Chieti; ³ Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome; and ⁴ National Institute for Cure and Study of Tumours, Milan, Italy

Requests for reprints: Gabriella D'Orazi, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. Phone: 39-6-5266-2563; Fax: 39-6-5266-2505; E-mail: dorazi{at}ifo.it.

Purpose: Homeodomain-interacting protein kinase-2 (HIPK2), a corepressor for homeodomain transcription factors, is a multifunctional kinase whose role in tumor cell survival is not completely clarified. We addressed whether HIPK2 restrains colon tumorigenesis by turning off cytosolic phospholipase A₂ (cPLA₂)-dependent prostaglandin E₂ (PGE₂) generation in the light of overwhelming evidence suggesting the contribution of this prostanoid in a variety of cancers.

Experimental Design: In the human colorectal cancer cell line, RKO, we studied the effect of RNA interference for HIPK2 (HIPK2i) on prostanoid biosynthesis, both in the absence and in the presence of the cPLA₂ inhibitor arachidonyl trifluoromethyl ketone. We evaluated the role of HIPK2 in the cPLA₂ gene regulation by reverse transcriptase-PCR, transcriptional activity, and chromatin immunoprecipitation analyses. The involvement of HIPK2 in tumorigenicity in vivo was studied by tumor growth of HIPK2i cells in nude mice. We compared the gene expression of HIPK2 and cPLA₂ in human colorectal cancer specimens by reverse transcriptase-PCR.

Results: HIPK2 silencing was associated with rousing PGE₂ biosynthesis that was profoundly suppressed by the cPLA₂ inhibitor. HIPK2 overexpression, along with histone deacetylase-1, inhibited the cPLA₂-luc promoter that is strongly acetylated in HIPK2i cells. The tumors derived from HIPK2i cells injected in nude mice showed noticeably increased growth compared with parental cells. HIPK2 mRNA levels were significantly higher in colorectal cancers of patients with familial adenomatous polyposis, which showed undetectable cPLA₂ levels compared with sporadic colorectal cancer expressing cPLA₂.

Conclusions: Our findings reveal the novel mechanism of HIPK2 to restrain progression of human colon tumorigenesis, at least in part, by turning off cPLA₂-dependent PGE₂ generation.

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