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Lentiviral vector expressing a validated shRNA against human MYC from the Mission shRNA Library (TRCN0000039642) was subcloned in a Plko Tet-On inducible system (Addgene plasmid # 21915 ref.
#LZIP PGC1A SOFTWARE#
For ESRRA deletion, single-guide RNA (sgRNA) constructs targeting ESRRA (sgERRα#1: 5′CTCCGGCTACCACTATGGTGTGG3′ sgERRα#2: 3′AGGAACCCTTTGGACTGTCAGGG5′) were designed using Crispor software () and cloned in a lentiviral vector purchased from Addgene LentiCRISPR V2 (a gift from Mohan Babu, Addgene plasmid # 83480). For PGC1A expression, cells were transduced with a modified TRIPZ (Dharmacon) doxycycline-inducible lentiviral construct in which the red fluorescent protein and miR30 region was substituted by HA-Flag-Pgc1a ( 9). DU145, PC3, and 293FT cell lines were maintained in DMEM supplemented with 10% volume for volume (v/v) FBS and 1% (v/v) penicillin–streptomycin. All cell lines were routinely monitored for Mycoplasma contamination. 293FT cells were used for lentiviral production. None of the cell lines used in this study were found in the database of commonly misidentified cell lines maintained by the International Cell Line Authentication Committee and NCBI Biosample. Cell lines where periodically subjected to microsatellite-based identity validation. Human prostate carcinoma cell lines PC3 and DU145 were purchased from Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, who provided authentication certificate. Altogether, these results support that PGC1α–ERRα functions as a tumor-suppressive transcriptional complex through the regulation of metabolic and signaling events. The inverse correlation between PGC1α–ERRα activity and MYC levels was corroborated in multiple prostate cancer datasets. In addition, PGC1α and ERRα associated at the MYC promoter, supporting the inhibitory activity PGC1α. Mechanistically, PGC1α expression decreased MYC levels and activity prior to inhibition of invasiveness. CRISPR/Cas9-based deletion of ERRα suppressed PGC1α regulation of cytoskeletal organization and invasiveness. This phenotype was consistent with remarkable cytoskeletal remodeling and inhibition of integrin alpha 1 and beta 4 expression, both in vitro and in vivo. PGC1α expression significantly decreased migration and invasion of various prostate cancer cell lines. Here we show that the transcriptional complex formed by PGC1α and estrogen-related receptor 1 alpha (ERRα) controls the aggressive properties of prostate cancer cells. PGC1A downregulation in prostate cancer is causally associated with the development of metastasis. The PPARγ coactivator 1 alpha (PGC1α) is a prostate tumor suppressor that controls the balance between anabolism and catabolism.