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Mitochondrial metabolism is inhibited by the HIF 1α‐ MYC ‐ PGC ‐1β axis in BRAF V600E thyroid cancer
Author(s) -
Gao Yanyan,
Yang Fang,
Yang XiuAn,
Zhang Li,
Yu Huixin,
Cheng Xian,
Xu Shichen,
Pan Jie,
Wang Kun,
Li Peifeng
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14786
Subject(s) - thyroid cancer , cancer research , glycolysis , cancer , v600e , papillary thyroid cancer , biology , thyroid , chemistry , endocrinology , microbiology and biotechnology , medicine , mutation , biochemistry , metabolism , gene
BRAF V600E is the most common mutation identified in thyroid cancers. However, the relationship between BRAF V600E and metabolic reprogramming in thyroid cancer is unclear. Here, we investigate the mechanism of metabolic reprogramming in BRAF V600E thyroid cancer by constructing BRAF V600E‐overexpressing and BRAF ‐knockdown thyroid cell lines for use in mitochondrial respiration and glycolysis experiments. Western blot and RT ‐ qPCR were performed to measure the level of metabolism‐related proteins, and various approaches were used to investigate transcriptional regulation. In thyroid cancer cells, the overexpression of BRAF V600E inhibited OXPHOS gene expression and mitochondrial respiration but enhanced aerobic glycolysis. Clinical thyroid cancer samples carrying the BRAF V600E mutation had suppressed levels of PGC ‐1β but increased expression of HIF 1α. Our results show that BRAF V600E reduced mitochondrial respiration by decreasing the expression of PGC ‐1β. In addition, HIF 1α, which is a target of BRAF V600E, was found to regulate the expression of PGC ‐1β via MYC . Furthermore, glycolysis‐related enzymes, such as LDHA and PKM 2, were upregulated in BRAF V600E mutant thyroid cancer specimens, thereby promoting glycolysis. MEK 1/2 inhibitor treatment enhanced the specific dependence of BRAF V600E mutant thyroid cancer on mitochondrial respiration. These results indicate that in thyroid cancer, the BRAF V600E mutation alters the HIF 1α‐ MYC ‐ PGC ‐1β axis, causing mitochondrial respiration to be inhibited and aerobic glycolysis to be enhanced.