12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression. The FASEB Journal, March 10, 2016. Kenneth V. Honn, Yande Guo, Yinlong Cai, Menq-Jer Lee, Gregory Dyson, Wenliang Zhang, and Stephanie C. Tucker.
Department of Pathology, Wayne State University, Detroit, Michigan
Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan
Department of Chemistry, Wayne State University, Detroit, Michigan
Biostatics Core, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University, School of Medicine and Simmons Cancer Institute, Springfield, IL
University of North Carolina Greensboro Center for Translational Biomedical Research, Kannapolis, NC
Previously we identified and deorphaned G-protein-coupled receptor 31 (GPR31) as the high-affinity 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] receptor (12-HETER1). Here we have determined its distribution in prostate cancer tissue and its role in prostate tumorigenesis using in vitro and in vivo assays. Data-mining studies strongly suggest that 12-HETER1 expression positively correlates with the aggressiveness and progression of prostate tumors. This was corroborated with real-time PCR analysis of human prostate tumor tissue arrays that revealed the expression of 12-HETER1 positively correlates with the clinical stages of prostate cancers and Gleason scores. Immunohistochemistry analysis also proved that the expression of 12-HETER1 is positively correlated with the grades of prostate cancer. Knockdown of 12-HETER1 in prostate cancer cells markedly reduced colony formation and inhibited tumor growth in animals. To discover the regulatory factors, 5 candidate 12-HETER1 promoter cis elements were assayed as luciferase reporter fusions in Chinese hamster ovary (CHO) cells, where the putative cis element required for gene regulation was mapped 2 kb upstream of the 12-HETER1 transcriptional start site. The data implicate 12-HETER1 in a critical new role in the regulation of prostate cancer progression and offer a novel alternative target for therapeutic intervention.—Honn, K. V., Guo, Y., Cai, Y., Lee, M.-J., Dyson, G., Zhang, W., Tucker, S. C. 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression.