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–PGC1α 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–PGC1α axis transcription. More importantly, the combined inhibition of ACLY sensitized BRAF -mutant melanoma to MAPK inhibition by suppressing MITF–PGC1α 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.

中文翻译：

---

ATP-柠檬酸裂解酶表观遗传增强氧化磷酸化以促进黑色素瘤生长和对 MAPK 抑制的适应性抵抗。

目的：增强的脂肪生成和线粒体功能是黑色素瘤的两个关键代谢特征，但它们在肿瘤生物学和靶向治疗中的串扰仍然未知。ATP-柠檬酸裂解酶 (ACLY) 是一种关键的脂肪生成酶，与肿瘤发展密切相关，但其在线粒体功能和黑色素瘤发病机制中的作用尚未阐明。实验设计：进行体外和体内功能实验以确定ACLY对黑色素瘤生长的影响。使用 mRNA 表达谱分析和一组生化分析来研究 ACLY 在线粒体氧化磷酸化中的作用及其潜在机制。还检查了联合 ACLY 抑制对 MAPK 抑制治疗功效的影响。结果：我们首先发现 ACLY 表达在黑色素瘤中增加，并在体外和体内促进细胞增殖和肿瘤生长。随后的 mRNA 表达谱分析和功能研究表明，ACLY 特异性激活 MITF-PGC1α 轴以促进线粒体生物发生和黑色素瘤生长。从机制上讲，ACLY 增强了乙酰转移酶 P300 的活性，增加了 MITF 基因座的组蛋白乙酰化以促进 MITF-PGC1α 轴转录。更重要的是，ACLY 的联合抑制通过抑制 MITF-PGC1α 轴使 BRAF 突变黑色素瘤对 MAPK 抑制敏感。结论：我们证明 ACLY 表观遗传增强氧化磷酸化以促进黑色素瘤生长和 MAPK 抑制适应性抵抗。