COBLL1 modulates cell morphology and facilitates androgen receptor genomic binding in advanced prostate cancer
Menée in vitro et in vivo sur des modèles de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, en interaction avec le récepteur des androgènes, la protéine COBLL1 favorise la prolifération et la migration des cellules cancéreuses, ainsi que la progression d'une tumeur vers la résistance à la castration
Activated androgen receptor signaling is a key driver to circumvent androgen-deprivation therapy in advanced prostate cancer. Cordon-bleu (COBL) has been identified as a specific player in morphogenesis by regulating actin networks in neurons. Here, we identify another COBL protein, COBL-like 1 (COBLL1), as an important factor that contributes to prostate cancer progression by stimulating androgen receptor signaling and modulating cell morphology. We show that COBLL1 is regulated by androgen and is highly up-regulated in treatment-resistant prostate cancer model cells, where COBLL1 mediates cell proliferation and migration, supporting a fundamental role for COBLL1 in prostate cancer. Our study shows the potential implications for therapeutic targeting of COBLL1 in advanced prostate cancer. Androgen receptor (AR) signaling is essential for prostate cancer progression and acquiring resistance to hormone therapy. However, the molecular pathogenesis through AR activation has not been fully understood. We performed integrative transcriptomic analysis to compare the AR program in a castration-resistant prostate cancer (CRPC) model with that in their parental hormone-sensitive cells. We found that the gene cordon-bleu–like 1 (COBLL1) is highly induced by AR in CRPC model cells. The expression of COBLL1 that possesses an actin-binding domain is up-regulated in clinical prostate cancer tissues and is associated with a poor prognosis for prostate cancer patients. COBLL1 is involved in the cancer cell morphogenesis to a neuron-like cell shape observed in the CRPC model cells, promoting cell growth and migration. Moreover, nuclear COBLL1 interacts with AR to enhance complex formation with CDK1 and facilitates AR phosphorylation for genomic binding in CRPC model cells. Thus, our findings showed the mechanistic relevance of cordon-bleu proteins during the AR-mediated progression to CRPC.