1198 ATP-citrate lyase contributes to melanoma growth and MAPK inhibitors resistance by epigenetically regulating MITF and oxidative phosphorylation

Abstract

Melanoma is the most life-threatening skin cancer for its rapid progression and frequent resistance to BRAF/MEK inhibitors. Enhanced lipogenesis and mitochondria function are two hallmark metabolic characteristics of melanoma, but their crosstalk in regulating melanoma growth and MAPK inhibitors resistance has not been elucidated. ATP-citrate lyase (ACLY) is a critical enzyme in lipogenesis by producing acetyl-CoA, the building block for fatty acid synthesis. Herein, we first found that ACLY expression was significantly increased in melanoma and highly correlated with poor clinical outcomes. Then, the knockdown of ACLY markedly attenuated cell proliferation in vitro and suppressed tumor growth in vivo. Subsequently, through the genome-wide mRNA profile analysis, we found that ACLY specifically regulated the expression of melanocytic lineage transcription factor MITF and its downstream PGC1α. The oncogenic role of ACLY was dependent on mitochondrial oxidative phosphorylation mediated by MITF-PGC1α axis. More importantly, ACLY conferred resistance to BRAF/MEK inhibitors by potentiating MITF-PGC1α axis and mitochondria function, and the combination treatment with ACLY inhibitor sensitized BRAF mutant melanoma to MAPK inhibition. Further mechanistic study revealed that ACLY regulated acetyltransferase P300 activity, increasing the histone acetylation at the MITF locus, thus activating MITF transcription and mitochondria biogenesis. Altogether, our results demonstrate that ACLY contributes to melanoma growth and MAPK inhibitors resistance by epigenetically regulating MITF and oxidative phosphorylation, providing a novel linkage between lipid metabolism and mitochondria function in tumor biology.