1. PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control
- Author
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Ariane Schaub-Clerigué, Antonio Gómez-Muñoz, Verónica Torrano, Laura Camacho, Eva Crosas-Molist, Alice Macchia, Lorea Valcarcel-Jimenez, Victoria Sanz-Moreno, Ana R. Cortazar, Ivana Hermanova, Paolo Cicogna, Sonia Fernández-Ruiz, Cristina Viera-Bardón, Irene Rodriguez-Hernandez, Arkaitz Carracedo, Natalia Martín-Martín, Ianire Astobiza, and Jon Corres-Mendizabal
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Transcription, Genetic ,Datasets as Topic ,Biology ,law.invention ,Metastasis ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Downregulation and upregulation ,Prostate ,law ,Cell Movement ,Cell Line, Tumor ,Coactivator ,Transcriptional regulation ,medicine ,Humans ,Neoplasm Invasiveness ,Promoter Regions, Genetic ,Cell Proliferation ,Regulation of gene expression ,Prostatic Neoplasms ,medicine.disease ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Cancer research ,Suppressor ,Signal Transduction - Abstract
The PPARγ coactivator 1 alpha (PGC1α) 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 PGC1α and estrogen-related receptor 1 alpha (ERRα) controls the aggressive properties of prostate cancer cells. PGC1α 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 ERRα suppressed PGC1α regulation of cytoskeletal organization and invasiveness. Mechanistically, PGC1α expression decreased MYC levels and activity prior to inhibition of invasiveness. In addition, PGC1α and ERRα associated at the MYC promoter, supporting the inhibitory activity PGC1α. The inverse correlation between PGC1α–ERRα activity and MYC levels was corroborated in multiple prostate cancer datasets. Altogether, these results support that PGC1α–ERRα 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.
- Published
- 2019