Fine-Tuning Lipid Metabolism by Targeting Mitochondria-Associated Acetyl-CoA-Carboxylase 2 in Papillary Thyroid Carcinoma.

BRAF acts as an ATP-dependent cytosolic kinase. BRAF inhibitors are widely available, but resistance to them is widely reported in the clinic. Lipid metabolism (fatty acids) is fundamental for energy and to control cell stress. Whether and how BRAF impacts lipid metabolism regulation in papillary thyroid carcinoma (PTC) is still unknown. Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme for lipid synthesis and inhibition of fatty acid oxidation (FAO). and genes encode distinct isoforms of ACC. The aim of our study was to determine the relationship between BRAF and ACC in PTC. We performed RNA-seq and DNA copy number analyses in PTC and normal thyroid (NT) in The Cancer Genome Atlas samples. Validations were performed by using assays on PTC-derived cell lines of differing status and a xenograft mouse model derived from a heterozygous PTC-derived cell line with knockdown (sh) of or . mRNA expression was significantly downregulated in -PTC vs. -PTC or NT clinical samples. ACC2 protein levels were downregulated in -PTC cell lines vs. the BRAF PTC cell line. Vemurafenib increased (and to a lesser extent ACC1) mRNA levels in PTC-derived cell lines in a allelic dose-dependent manner. BRAF inhibition increased lipid synthesis rates, and decreased FAO due to oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), after addition of palmitate. Only sh significantly increased OCR rates due to FAO, while it decreased ECAR in BRAF PTC-derived cells vs. controls. BRAF inhibition synergized with sh to increase intracellular reactive oxygen species production, leading to increased cell proliferation and, ultimately, vemurafenib resistance. Mice implanted with a BRAF PTC-derived cell line with sh showed significantly increased tumor growth after vemurafenib treatment, while vehicle-treated controls, or shGFP control cells treated with vemurafenib showed stable tumor growth. These findings suggest a potential link between BRAF and lipid metabolism regulation in PTC. BRAF downregulates ACC2 levels, which deregulates lipid synthesis, FAO due to OCR, and ECAR rates. Sh may contribute to vemurafenib resistance and increased tumor growth. ACC2 rescue may represent a novel molecular strategy for overcoming resistance to BRAF inhibitors in refractory PTC.