Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transforms p53-mutant zebrafish melanocytes and co-operates with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induces oxidative stress in melanoma cells, which adapt by up-regulating cellular reactive oxygen species defenses. We show that inhibiting both DGAT1 and superoxide dismutase 1 profoundly suppress tumor growth through eliciting intolerable oxidative stress.

细胞代谢失调是癌症的一个标志，目前尚未确定可药物化的癌蛋白靶点。脂肪酸 (FA) 获取的增加使癌细胞能够满足其增强的膜生物发生、生物能量和信号传导需求。过量的 FA 对非转化细胞有毒，但令人惊讶的是对癌细胞没有毒性。这种癌症适应的分子可能提供替代药物靶点。在这里，我们证明二酰甘油O -酰基转移酶 1 (DGAT1) 是三酰甘油合成和脂滴形成不可或缺的酶，在黑色素瘤中经常上调，使黑色素瘤细胞能够耐受过量的 FA。 DGAT1 过表达单独会转化 p53 突变斑马鱼黑色素细胞，并与致癌 BRAF 或 NRAS 协同作用，以更快地形成黑色素瘤。 DGAT1 的拮抗作用会诱导黑色素瘤细胞中的氧化应激，从而通过上调细胞活性氧防御来适应。我们发现，抑制 DGAT1 和超氧化物歧化酶 1 可通过引发无法耐受的氧化应激来显着抑制肿瘤生长。