PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

The PPAR gamma coactivator 1 alpha (PGC1 alpha) is a prostate tumor suppressor that controls the balance between anabolism and catabolism. PGC1A downregulation in prostate cancer is causally associated with the development of metastasis. Here we show that the transcriptional complex formed by PGC1 alpha and estrogen-related receptor 1 alpha (ERR alpha) controls the aggressive properties of prostate cancer cells. PGC1 alpha expression significantly decreased migration and invasion of various prostate cancer cell lines. This phenotype was consistent with remarkable cytoskeletal remodeling and inhibition of integrin alpha 1 and beta 4 expression, both in vitro and in vivo. CRISPR/Cas9-based deletion of ERRa suppressed PGC1 alpha regulation of cytoskeletal organization and invasiveness. Mechanistically, PGC1 alpha expression decreased MYC levels and activity prior to inhibition of invasiveness. In addition, PGC1 alpha and ERR alpha associated at the MYC promoter, supporting the inhibitory activity PGC1 alpha. The inverse correlation between PGC1 alpha-ERR alpha activity and MYC levels was corroborated in multiple prostate cancer datasets. Altogether, these results support that PGC1 alpha-ERR alpha functions as a tumor-suppressive transcriptional complex through the regulation of metabolic and signaling events. Significance: These findings describe how downregulation of the prostate tumor suppressor PGC1 drives invasiveness and migration of prostate cancer cells.