Nuclear receptor coactivator 1 (NCOA1) is involved in the regulation of PCa cell migration via PRKD1

Due to the urgent need of new targeting strategies in PCa, AR interacting proteins should be considered. In this study we aimed to test the effect of a long-term knockdown of NCOA1, an AR coactivator, in PCa progression and metastatogenesis and whether NCOA1 could be used as a possible therapeutic target. To test the consequences of NCOA1 knockdown on proliferation, we performed by 3H thymidine incorporation assays revealing a strong reduction in castration resistant MDA PCa 2b and androgen-dependent LNCaP cells, without affecting AR negative PC3 cells. Furthermore, Boyden chamber assays revealed a strong decrease in migration and invasion upon NCOA1 knockdown. Using a cDNA microarray, we identified protein kinase D1 (PRKD1) as one prominent upregulated gene in MDA PCa 2b, which was not seen in PC3 cells. Knockdown of PRKD1 clearly reverted the reduced migratory potential. Moreover, we found phospholipase A2, group7 (PLA2G7) and eukaryotic translation initiation factor 5A2 (EIF5A2), which might be involved in migration of PC3 cells. Further, we can clearly demonstrate that PRKD1 is negatively regulated by the AR/NCOA1 complex. In addition, immunhistochemical staining revealed a strong increase in NCOA1 expression in matched and unmatched patients samples, respectively between normal prostate and primary tumor. Regarding the PRKD1 staining, no final conclusion can be drawn in terms of a tumor suppressor function. Thus, our findings directly associate NCOA1/AR complex with PRKD1 regulation and further suggest NCOA1 as a potential therapeutic target also due to the effect on PC3 cell migration.

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Luef B, Handle F, Kharaishvili G, Hager M, Rainer J, Janetschek G, Hruby S, Englberger C, Bouchal J, Santer FR, Culig Z