Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer

Area of Science:

• Molecular Oncology
• Cancer Metabolism
• Endocrine Signaling

Background:

• The role of androgen signaling in prostate cancer's oncometabolic state is not fully understood.
• Estrogen-related receptor γ (ERRγ) is implicated in cellular metabolism, but its function in prostate cancer is unclear.

Purpose of the Study:

• To elucidate how androgen signaling influences prostate cancer cell metabolism via estrogen-related receptor γ (ERRγ).
• To investigate the potential of targeting ERRγ signaling as a therapeutic strategy for prostate cancer.

Main Methods:

• Analysis of gene expression, protein binding events, and motif analyses in prostate cancer cells following androgen exposure.
• Assessment of metabolic pathway activity, including aerobic glycolysis, mitochondrial respiration, and lipid synthesis.
• Correlation of ERRγ expression levels with disease severity in clinical prostate cancer samples.

Main Results:

• Androgen treatment of prostate cancer cells increased aerobic glycolysis, mitochondrial respiration, and lipid synthesis.
• A metabolic gene expression signature linked to ERRγ action was identified, paralleling decreased ERRγ expression.
• Reduced ERRγ expression and increased metabolic activity were observed in both androgen-dependent and castration-resistant prostate cancer, correlating with cell proliferation and disease severity.

Conclusions:

• Androgen-dependent repression of ERRγ reprograms prostate cancer cell metabolism, enhancing mitochondrial activity and promoting cell proliferation.
• Reactivating ERRγ signaling presents a potential generalized therapeutic approach for prostate cancer management.