Low expression of PGC-1β and other mitochondrial biogenesis modulators in melanoma is associated with growth arrest and the induction of an immunosuppressive gene expression program dependent on MEK and IRF-1. (10th August 2022)

• Record Type: Journal Article
• Authors: Laurin, Karl M.; Coutu-Beaudry, Katherine; Salazar, Alejandro; Méribout, Nour; Audet-Walsh, Étienne; Gravel, Simon-Pierre
• Is Part Of: Cancer letters. Volume 541(2022)
• Publication Date: 2022-08-10
• Subjects: Melanoma -- Mitochondrial dysfunction -- Immunosuppression signature -- PGC-1 -- IRF-1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215738
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Mitochondria are specialized metabolic and immune organelles that have important roles in tumor progression, metastasis, and response to chemotherapy and immunotherapy. Mitochondrial biogenesis and functions are under the control of the peroxisome-proliferator activated receptor-gamma (PGC-1) transcriptional coactivators. Recent research unveiled the role of PGC-1α in bolstering mitochondrial oxidative functions and in the suppression of metastasis in melanoma, but the role of PGC-1s in tumor immunology remains elusive. Herein, we show that low PGC-1s expression in human melanoma tumors is associated with increased expression of a repertoire of immunosuppressive (CD73, PD-L2, Galectin-9) and pro-inflammatory (IL-8, TNF, IL-1β) transcripts, and that experimental depletion of PGC-1β recapitulates this signature in human melanoma cell lines. The depletion of PGC-1β reduces the expression of HSPA9, impairs mitochondrial activity, and leads to cell cycle arrest. Using pharmacological and gene silencing approaches, we further show that MEK1/2 and IRF-1 mediate the observed immune transcriptional response. Overall, this research suggests that mitochondrial biogenesis modulators can modulate tumor progression, immune evasion, and response to therapeutics through transcriptional control of immune pathways. Research Highlights: There is a negative correlation between mitochondrial biogenesis and immunosuppression signatures in melanoma. PGC-1β knockdown induces the expression of immunosuppression genes in melanoma cells PGC-1β knockdown leads to cell cycle arrest and reduces mitochondrial respiration IKKβ and MEK1/2 inhibition antagonizes the induction of immunosuppression markers PGC-1β knockdown induces nuclear accumulation of RelA/p65 and IRF-1