Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536-0509, USA.
Cell Death Dis. 2018 Feb 15;9(3):265. doi: 10.1038/s41419-018-0330-6.
Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in colon cancer cells. Bioenergetic analysis revealed that silencing SREBP1 or SREBP2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation indicating an alteration in cellular metabolism. Consequently, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension culture were significantly decreased. Similar results were obtained in colon cancer cells in which the proteolytic activation of SREBP was blocked. Importantly, knockdown of either SREBP1 or SREBP2 inhibited xenograft tumor growth in vivo and decreased the expression of genes associated with cancer stem cells. Taken together, our findings establish the molecular basis of SREBP-dependent metabolic regulation and provide a rationale for targeting lipid biosynthesis as a promising approach in colon cancer treatment.
固醇调节元件结合蛋白（SREBPs）属于转录因子家族，可调节脂肪酸和胆固醇合成所需基因的表达。哺乳动物细胞中已鉴定出三种 SREBP 同工型，即 SREBP1a、SREBP1c 和 SREBP2。SREBP1a 和 SREBP1c 通过使用不同的转录起始位点从单个基因衍生而来。在这里，我们研究了 SREBP 介导的脂肪生成在调节结肠癌肿瘤生长和起始中的作用。敲低 SREBP1 或 SREBP2 会降低脂肪酸水平，这是由于 SREBP 靶基因的表达减少，这些基因是脂质生物合成所必需的。生物能量分析显示，沉默 SREBP1 或 SREBP2 的表达会降低线粒体呼吸、糖酵解以及脂肪酸氧化，表明细胞代谢发生了改变。因此，细胞增殖速度以及癌细胞在悬浮培养中形成肿瘤球体的能力显著降低。在 SREBP 蛋白水解激活被阻断的结肠癌细胞中也获得了类似的结果。重要的是，敲低 SREBP1 或 SREBP2 均可抑制体内异种移植物肿瘤的生长，并降低与癌症干细胞相关的基因的表达。总之，我们的研究结果确立了 SREBP 依赖性代谢调节的分子基础，并为将脂质生物合成作为结肠癌治疗的一种有前途的方法提供了依据。
