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

• Published in: The FASEB journal 2016-06, Vol.30 (6), p.2360-2369
• Main Authors: Honn, Kenneth V., Guo, Yande, Cai, Yinlong, Lee, Menq‐Jer, Dyson, Gregory, Zhang, Wenliang, Tucker, Stephanie C.
• Format: Article
• Language: English
• Subjects: 12(S)‐HETE; Animals; arachidonate metabolism in malignancy; Cell Line; Cloning, Molecular; Computational Biology; Cricetinae; Databases, Factual; Gene Expression Regulation, Neoplastic - physiology; Humans; inflammatory pathway; Male; Promoter Regions, Genetic; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Receptors, Eicosanoid - genetics; Receptors, Eicosanoid - metabolism; Receptors, G-Protein-Coupled - classification; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Tissue Array Analysis; Transcriptome; Up-Regulation - physiology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201500076

ABSTRACT 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. FASEB J. 30, 2360–2369 (2016). www.fasebj.org