YAP coordinates lipid and cholesterol metabolism in papillary thyroid cancer through a glucose–AMPK-gated TEAD1–SREBP1/2 axis

Abstract

To determine whether Yes-associated protein (YAP), a transcriptional coactivator frequently activated in cancer, coordinates lipid and cholesterol metabolism in papillary thyroid cancer (PTC), YAP was overexpressed or silenced in BCPAP and TPC-1 cells, and transcriptomic, biochemical and functional analyses were performed. Glucose deprivation and the AMP-activated protein kinase (AMPK) activator metformin suppressed YAP nuclear localization and lipogenic programs, whereas AMPK inhibition by Compound C or YAP overexpression (OE) restored them. Mechanistically, YAP associated with TEA domain family member 1 (TEAD1), occupied canonical TEAD-binding motifs in the SREBF1 and SREBF2 promoters, and activated their transcription in a TEAD1-dependent manner: TEAD1 knockdown abolished YAP-induced SREBF promoter activity, while eight-group genetic epistasis experiments showed that TEAD1 or SREBP1/2 depletion was required for YAP-driven proliferation, clonogenic growth, neutral-lipid and cholesterol accumulation, and expression of FASN, SCD, HMGCR and HMGCS1. Pharmacological SREBP blockade by fatostatin or AMPK activation by metformin reversed YAP-driven phenotypes in vitro and restrained xenograft growth in vivo, with comparable tumor-weight inhibition between the two treatments and no effect on body weight.Clinically, YAP1 expression correlated with lipogenic genes and with shorter disease-free survival in the TCGA-THCA cohort and with SREBP expression in 200 paired PTC specimens. These findings support a model in which glucose–AMPK signaling gates a YAP–TEAD1–SREBP1/2 axis that promotes lipid and cholesterol metabolism and PTC growth, and suggest metformin and SREBP-targeting strategies as candidate therapeutic approaches.