Protein Arginine Methyltransferase 5 in Castration-Resistant and Neuroendocrine Prostate Cancer

Abstract

Prostate cancer is one of the most frequently diagnosed cancers and the second leading cause of cancer-related deaths in male population. While localized prostate cancer can be successfully treated with surgery or radiation therapy, the metastatic disease has no curable options. Metastasis can be developed as a result of failed therapy of localized cancer or present at initial diagnosis. As metastasis is the most common cause of prostate cancer-related death, developing novel approaches and improving the efficiency of existing therapies for the metastatic prostate cancer treatment will significantly improve patients’ survival. The first-line treatment option for metastatic prostate cancer and localized prostate cancer with high risk of recurrence is androgen deprivation therapy (ADT) that decreases androgen receptor (AR) signaling. However, targeting AR signaling inevitably leads to AR reactivation and cancer progression to the castration-resistant prostate cancer (CRPC) that has no curable treatment options. Moreover, about 30% of CRPC cases progress to neuroendocrine prostate cancer (NEPC), highly aggressive and lethal type of prostate cancer. Recently my group has shown that protein arginine methyltransferase 5 (PRMT5) functions as an activator of AR expression in hormone-naive prostate cancer (HNPC). In this dissertation, I demonstrate that PRMT5 also functions as an epigenetic activator of AR transcription in CRPC via symmetric dimethylation of H4R3 at the AR promoter. This epigenetic activation is dependent on pICln, a PRMT5 interaction partner involved in spliceosome assembly, and independent of MEP50, the canonical cofactor of PRMT5. PRMT5 and pICln, but not MEP50, were required for the expression of AR signaling pathway genes. In clinical samples of both HNPC and CRPC, nuclear PRMT5 and pICln protein expressions were highly positively correlated with nuclear AR protein expression. In xenograft tumors, targeting PRMT5 or pICln significantly decreased tumor growth and AR expression. Overall, this work identifies PRMT5/pICln as a therapeutic target for HNPC and CRPC treatment that needs to be further evaluated in clinical setting.