Low expression of PGC-1ß 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.
Cancer Lett
; 541: 215738, 2022 08 10.
Article
em En
| MEDLINE
| ID: mdl-35594996
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-1ß) transcripts, and that experimental depletion of PGC-1ß recapitulates this signature in human melanoma cell lines. The depletion of PGC-1ß 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Biogênese de Organelas
/
Proteínas de Ligação a RNA
/
Melanoma
/
Mitocôndrias
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article