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MIEF2 reprograms lipid metabolism to drive progression of ovarian cancer through ROS/AKT/mTOR signaling pathway

MIEF2 (mitochondrial elongation factor 2) is one of the key regulators of mitochondrial fission. Bioinformatics analysis indicated that high expression of MIEF2 predicted a poor prognosis in ovarian cancer patients. However, the relationship between MIEF2 and aberrant lipid metabolism in OC remains...

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Detalles Bibliográficos
Autores principales: Zhao, Shuhua, Cheng, Lu, Shi, Yuan, Li, Jia, Yun, Qinghui, Yang, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791105/
https://www.ncbi.nlm.nih.gov/pubmed/33414447
http://dx.doi.org/10.1038/s41419-020-03336-6
Descripción
Sumario:MIEF2 (mitochondrial elongation factor 2) is one of the key regulators of mitochondrial fission. Bioinformatics analysis indicated that high expression of MIEF2 predicted a poor prognosis in ovarian cancer patients. However, the relationship between MIEF2 and aberrant lipid metabolism in OC remains elusive. In this study, we demonstrated that MIEF2 significantly promoted lipid synthesis, while has no significant effect on fatty acid uptake and oxidation in OC cells. MIEF2 enhanced de novo fatty acid synthesis through up-regulating the expression of sterol regulatory element binding protein 1 (SREBP1) and its transcriptional target lipogenic genes ACC1, FASN and SCD1. Meanwhile, MIEF2-promoted cholesterol biosynthesis through up-regulating the expression of sterol regulatory element binding protein 2 (SREBP2) and its transcriptional target cholesterol biosynthesis genes HMGCS1 and HMGCR. Mechanistically, increased mitochondrial reactive oxygen species (ROS) production and subsequently activation of AKT/mTOR signaling pathway was found to be involved in the up-regulation of SREBP1 and SREBP2 in OC cells. Moreover, cell growth and metastasis assays indicated that MIEF2-regulated fatty acid synthesis and cholesterol biosynthesis played a critical role in the progression of OC. Taken together, our findings indicate that MIEF2 is a critical regulator of lipid synthesis in OC, which provides a strong line of evidence for this molecule to serve as a drug target in the treatment of this malignancy.