MAEL facilitates metabolic reprogramming and breast cancer progression by promoting the degradation of citrate synthase and fumarate hydratase via chaperone-mediated autophagy.
FEBS J
; 290(14): 3614-3628, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-36866961
ABSTRACT
Metabolic reprogramming is a hallmark of cancer. Several studies have shown that inactivation of Krebs cycle enzymes, such as citrate synthase (CS) and fumarate hydratase (FH), facilitates aerobic glycolysis and cancer progression. MAEL has been shown to play an oncogenic role in bladder, liver, colon, and gastric cancers, but its role in breast cancer and metabolism is still unknown. Here, we demonstrated that MAEL promoted malignant behaviours and aerobic glycolysis in breast cancer cells. Mechanistically, MAEL interacted with CS/FH and HSAP8 via its MAEL domain and HMG domain, respectively, and then enhanced the binding affinity of CS/FH with HSPA8, facilitating the transport of CS/FH to the lysosome for degradation. MAEL-induced degradation of CS and FH could be suppressed by the lysosome inhibitors leupeptin and NH4 Cl, but not by the macroautophagy inhibitor 3-MA or the proteasome inhibitor MG132. These results suggested that MAEL promoted the degradation of CS and FH via chaperone-mediated autophagy (CMA). Further studies showed that the expression of MAEL was significantly and negatively correlated with CS and FH in breast cancer. Moreover, overexpression of CS or/and FH could reverse the oncogenic effects of MAEL. Taken together, MAEL promotes a metabolic shift from oxidative phosphorylation to glycolysis by inducing CMA-dependent degradation of CS and FH, thereby promoting breast cancer progression. These findings have elucidated a novel molecular mechanism of MAEL in cancer.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Autofagia Mediada por Chaperonas
Limite:
Female
/
Humans
Idioma:
En
Revista:
FEBS J
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China