Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Clin Cancer Res. 2020 Jun 1;26(11):2725-2739. doi: 10.1158/1078-0432.CCR-19-1359. Epub 2020 Feb 7.
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.
and 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.
We first found that ACLY expression was increased in melanoma and facilitated cell proliferation and tumor growth both and . 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 -mutant melanoma to MAPK inhibition by suppressing MITF-PGC1α axis.
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.
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相互作用尚不清楚。三磷酸腺苷柠檬酸裂解酶（ACLY）是一种关键的脂肪生成酶，与肿瘤的发展密切相关，但它在线粒体功能和黑色素瘤发病机制中的作用尚未阐明。
进行了和功能实验，以确定 ACLY 对黑色素瘤生长的影响。使用 mRNA 表达谱分析和一系列生化测定来研究 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 抑制治疗效果的影响。
我们首先发现 ACLY 在黑色素瘤中的表达增加，并促进了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。机制上，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 轴来增加 MAPK 抑制对 -突变黑色素瘤的敏感性。
我们证明 ACLY 通过表观遗传增强氧化磷酸化来促进黑色素瘤生长和 MAPK 抑制适应性耐药。我们的研究发现了肿瘤生物学中脂肪生成和线粒体功能之间的新的相互作用，并强调了通过同时损害肿瘤生长和 MAPK 抑制耐药性来靶向 ACLY 作为一种有效的治疗方法。
