DNA microarray analysis of HCT116 cells transfected with control or MYC siRNAs. Homo sapiens

Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here, we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multi-omics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS and CTPS blocked cell growth, and thus they are potential targets for colorectal cancer therapy. Overall design: Gene expression in HCT116 cells transfected with control or MYC siRNAs was measured. Four independent experiments were performed at each siRNA.

癌细胞会改变自身代谢以合成大分子前体物质，但目前人们对该代谢重编程背后的调控机制仍知之甚少。本研究表明，结直肠癌的代谢重编程主要由MYC基因（MYC）的异常表达所介导。本研究对275例结直肠癌患者的配对正常组织与肿瘤组织开展多组学分析后发现，代谢改变发生在癌变的腺瘤阶段，且其发生与结直肠癌癌变相关的特异性基因突变并无关联。MYC基因的表达可通过调控121个代谢基因与39个转运蛋白基因的表达水平，诱导至少215种代谢反应。此外，MYC基因可负调控参与线粒体生物发生与维持的基因表达，同时正调控参与DNA与组蛋白甲基化的基因。在结直肠癌细胞中敲低MYC基因可重置异常的代谢状态，并抑制细胞增殖。此外，抑制MYC靶向的嘧啶合成基因（如CAD、UMPS和CTPS）可阻断细胞增殖，因此这些基因可作为结直肠癌治疗的潜在靶点。研究整体设计：本研究检测了转染对照小干扰RNA（siRNA）或MYC siRNA的HCT116细胞中的基因表达水平，每个siRNA组均设置4次独立重复实验。