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.
Highlights
The process of cellular transformation stems from the acquisition of genomic aberrations that altogether change the response of normal cells and enable them with hallmarks of cancer [1, 2]
To address the role of PPARg coactivator 1 alpha (PGC1a) in the regulation of prostate cancer features beyond proliferation [17], we carried out a comprehensive evaluation of phenotypes associated to cancer aggressiveness, based on an inducible system reported previously [17]
Pgc1a expression elicited a remarkable reduction in the migratory capacity of PC3 and DU145 prostate cancer cells in transwell assays (Fig. 1A; Supplementary Fig. S1A)
Summary
The process of cellular transformation stems from the acquisition of genomic aberrations that altogether change the response of normal cells and enable them with hallmarks of cancer [1, 2]. The mutational landscape changes within and among tumors and along time following evolutionary principles [3]. Nongenomic alterations harness great relevance in the process of. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Macchia contributed to this article as first authors
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