PGC1a-driven transcriptional control of the cell secretome in prostate cancermolecular and biological analysis

Resumen

The transcriptional co-regulator peroxisome proliferator-activated receptor gamma co- activator 1 alpha (PGC1¿) was shown to exert a tumor suppressive role in prostate cancer (PCa) by means of regulating the balance between anabolism and catabolism. This anti-tumoral activity happened to be dependent on its partner oestrogen-related receptor alpha (ERR¿). Classically, the roles attributed to PGC1¿ under physiological and pathological conditions were linked to the regulation of metabolic processes. Yet, in the present work we have deciphered that the transcriptional reprogramming induced by PGC1¿ in PCa epithelial cells extends to novel functions. We show that the anti-tumoral effects of PGC1¿ seem to be driven by cell-intrinsic and cell-extrinsic phenomena that include the regulation of cell cycle, interferon response and the secretome composition. Indeed, secretome fractionation into extracellular vesicles (EVs) and soluble factors (SFs) revealed a differential protein composition upon expression of PGC1¿. This secretome fractionation also drove us to conclude that despite EVs produced by PGC1¿- expressing and non-expressing cells showed no distinct biological roles, they could be used as non-invasive bystanders of PCa progression. We also show that PGC1¿-driven SFs seem to promote metastasis formation in vivo. On the other hand, PGC1¿- ERR¿-regulated SFs were shown to suppress proliferation capacity of PCa cells in vitro. Overall, data further suggests that PGC1¿-regulated SFs (probably involving IFN-ß secretion) activate autocrine and paracrine tumor-suppressive mechanisms in PCa cells. Hence, due to the tumor suppressive role and stratification potential of PGC1¿, we believe that understanding its contribution on the regulation of the cell secretome could allow us to decipher the cell communication networks established between PCa epithelial cells and the stromal compartment. This could open new avenues for the identification of non-invasive biomarkers of PCa progression as well as the development of novel therapeutic strategies to treat aggressive PCa.