N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer

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.