ATP-citrate lyase epigenetically potentiates oxidative phosphorylation to promote melanoma growth and adaptive resistance to MAPK inhibition.

Purpose: Enhanced lipogenesis and mitochondrial function are two critical metabolic characteristics in melanoma, but their crosstalk involved in tumor biology and targeted therapy remains unknown. ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that is greatly implicated in tumor development, but its role in mitochondrial function and melanoma pathogenesis has not been elucidated. Experimental Design: In vitro and in vivo functional experiments were performed to determine the effect of ACLY on melanoma growth. mRNA expression profile analysis and a panel of biochemical assays were used to investigate the role of ACLY in mitochondrial oxidative phosphorylation and the underlying mechanism. The effect of combined ACLY inhibition on the efficacy of MAPK inhibition therapy was also examined. Results: We first found that ACLY expression was increased in melanoma and facilitated cell proliferation and tumor growth both in vitro and in vivo. Subsequent mRNA expression profile analysis and functional studies unveiled that ACLY specifically activated MITF-PGC1 alpha axis to promote mitochondrial biogenesis and melanoma growth. Mechanistically, ACLY enhanced the activity of acetyltransferase P300, increasing the histone acetylation at MITF locus to promote MITF-PGC1 alpha axis transcription. More importantly, the combined inhibition of ACLY sensitized BRAF-mutant melanoma to MAPK inhibition by suppressing MITF-PGC1 alpha axis. Conclusions: We demonstrate that ACLY epigenetically potentiates oxidative phosphorylation to promote melanoma growth and MAPK inhibition adaptive resistance. Our study discovers the novel crosstalk between lipogenesis and mitochondrial function in tumor biology and highlights targeting ACLY as a potent therapeutic approach via simultaneously impairing tumor growth and MAPK inhibition resistance in melanoma.