PGC1a suppresses prostate cancer cell invasion through ERRA transcriptional control

Abstract

The PPARg coactivator 1 alpha (PGC1a) 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 PGC1a and estrogen-related receptor 1 alpha (ERRa) controls the aggressive properties of prostate cancer cells. PGC1a 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 PGC1a regulation of cytoskeletal organization and invasiveness. Mechanistically, PGC1a expression decreased MYC levels and activity prior to inhibition of invasiveness. In addition, PGC1a and ERRa associated at the MYC promoter, supporting the inhibitory activity PGC1a. The inverse correlation between PGC1a–ERRa activity and MYC levels was corroborated in multiple prostate cancer datasets. Altogether, these results support that PGC1a–ERRa 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.