Elena Wild Thesis Final.pdf (5.41 MB)
Protein Arginine Methyltransferase 5 in Castration-Resistant and Neuroendocrine Prostate Cancer
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-naïve 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.
History
Degree Type
- Doctor of Philosophy
Department
- Medicinal Chemistry and Molecular Pharmacology
Campus location
- West Lafayette
