Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China; Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China.
Cancer Cell. 2018 Mar 12;33(3):368-385.e7. doi: 10.1016/j.ccell.2018.01.010. Epub 2018 Feb 15.
Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.
有氧糖酵解（瓦博格效应）促进肿瘤生长，目前正在开发针对有氧糖酵解的药物。然而，瓦博格效应是如何被直接调控的在很大程度上仍是未知的。在这里，我们发现转录因子 SIX1 可直接增加许多糖酵解基因的表达，从而促进体外和体内的瓦博格效应和肿瘤生长。SIX1 通过 HBO1 和 AIB1 组蛋白乙酰转移酶来调控糖酵解。与癌症相关的 SIX1 突变增加了其促进有氧糖酵解和肿瘤生长的能力。SIX1 的糖酵解功能可被 microRNA-548a-3p 直接抑制，而 microRNA-548a-3p 的下调与 SIX1 呈负相关，且是乳腺癌患者预后的良好预测因子。因此，microRNA-548a-3p/SIX1 轴将有氧糖酵解与致癌作用紧密联系起来，可能成为有前景的癌症治疗靶点。
