The protein arginine methyltransferases (PRMTs) PRMT1 and CARM1 as candidate epigenetic drivers in prostate cancer progression

Epigenetic changes are implicated in prostate cancer (PCa) progression and resistance to therapy. Arginine residue methylation is an understudied histone post-translational modification that is increasingly associated with cancer progression and is catalyzed by enzymes called protein arginine methyltransferases (PRMTs). The molecular consequences of aberrant expression of PRMTs in PCa and the relationship between PRMTs and PCa progression are largely unknown. Using immunohistochemistry, we examined the expression of PRMT1 and CARM1, two of the best-studied PRMTs, in 288 patients across the spectrum of PCa and correlated them with markers of androgen receptor (AR) signaling, and milestones of carcinogenesis. Our findings indicate that PRMT1 and CARM1 are upregulated early in PCa progression, and that CARM1 is further upregulated after therapy. In addition, a correlation of CARM1 with AR post-translational modifications was noted in the setting of therapy resistance, highlighting CARM1 as one of the adaptation mechanisms of PCa cells in an androgen-depleted environment. Finally, CARM1 correlated with markers of cell cycle regulation, and both CARM1 and PRMT1 correlated with markers of epithelial-to-mesenchymal transition signaling. Taken together these findings indicate that an epigenetic network drives PCa progression through enhancement of milestone pathways including AR signaling, the cell cycle, and epithelial-to-mesenchymal transition.