Mitochondrial metabolism is inhibited by the HIF1α‐MYC‐PGC‐1β axis in BRAF V600E thyroid cancer

Abstract

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 HIF1α. Our results show that BRAF V600E reduced mitochondrial respiration by decreasing the expression of PGC‐1β. In addition, HIF1α, 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 PKM2, were upregulated in BRAF V600E mutant thyroid cancer specimens, thereby promoting glycolysis. MEK1/2 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 HIF1α‐MYC‐PGC‐1β axis, causing mitochondrial respiration to be inhibited and aerobic glycolysis to be enhanced.

Long-term transcriptomic and proteomic effects in Sprague Dawley rat thyroid and plasma after internal low dose 131I exposure

“…LDHA catalyses the last step in aerobic glycolysis and is primarily located in muscle tissue, and APRT is an enzyme involved in the adenine nucleotide metabolism [32]. Furthermore, LDHA overexpression has been found in BRAF V600E-mutated thyroid cancer and inactivation of this protein can make cells more sensitive to radiation [38,39]. TGM3 is involved in the transformation of the cell envelope in epidermis and hair follicles, but it is also a tumour suppressor and has been proposed as a progression marker for radio-chemotherapy of head and neck cancers [32,40].…”

Metabolomic Reprogramming Detected by 1H-NMR Spectroscopy in Human Thyroid Cancer Tissues

“…Furthermore, it has also been observed that malignant thyroid lesions have lower citrate levels than benign ones [34,35], as also demonstrated in our results. Studies of in-vitro cultured cells suggest that oncogenic activation of BRAF (often mutated in thyroid cancer) inhibits OXPHOS in mitochondria and promotes aerobic glycolysis to sustain cancer cell growth [36]. Our findings, for the first time, hypothesize a connection between oxidative stress and the alteration of the metabolic profile in thyroid tumors.…”

Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome

“…PGC-1β regulates mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Moreover, MEK inhibitor increased OXPHOS-related genes in BRAF p.V600E mutated cell lines [189]. These findings suggest that oncogenic activation of BRAF inhibits OXPHOS in mitochondria and promotes aerobic glycolysis to sustain cancer cell growth.…”