N-Terminal Domain Mediated Regulation of ROR alpha 1 Inhibits Invasive Growth in Prostate Cancer

Abstract

Four members of the retinoic acid-related orphan receptor alpha (ROR alpha) family (ROR alpha 1, ROR alpha 2, ROR alpha 3 and ROR alpha 4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, ROR alpha 1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of ROR alpha 1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from ROR alpha-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in ROR alpha-deficient embryonic fibroblasts, and reconstitution of ROR alpha 1 inhibited this activation by a NTD dependent manner. Downregulation of ROR alpha 1 and upregulation of Wnt/beta-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated ROR alpha 1 signaling, suggesting advanced approaches for the development of therapeutic drugs.