PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs.
PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs.
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DOI：
10.1038/srep24324
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发表时间：
2016-04-15
影响因子：
4.6
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Chen L;Zhao J;Tang Q;Li H;Zhang C;Yu R;Zhao Y;Huo Y;Wu C
生物钟失调会促进癌症的生长。在这里，我们表明，PFKFB3，编码可诱导的6-磷酸果糖-2-激酶的基因，通过刺激糖酵解作为癌细胞生存的必要支持酶，介导了癌症发生的昼夜控制。在舌癌患者中，PFKFB3在癌组织及癌旁组织中的表达均显著高于对照组，并伴有核心昼夜节律基因的异常调节表达。在体外培养体系中，SCC9舌癌细胞表现出与对照KC细胞不同的PFKFB3和CLOCK的节律性表达。此外，CLOCK通过结合和增强PFKFB3启动子的转录活性来刺激PFKFB3在SCC9细胞中的表达。在ZT7(ZT7)抑制PFKFB3，而不是在ZT19(ZT19)抑制PFKFB3可显著降低乳酸产量和细胞增殖。一贯地，在昼夜时间(CT)7的小鼠中抑制PFKFB3，而不是CT19，显著地减少了植入性肿瘤的生长。综上所述，这些发现证明了PFKFB3是肿瘤生长的昼夜节律控制的中介，从而强调了基于时间的PFKFB3抑制在癌症治疗中的重要性。
Circadian clock dysregulation promotes cancer growth. Here we show that PFKFB3, the gene that encodes for inducible 6-phosphofructo-2-kinase as an essential supporting enzyme of cancer cell survival through stimulating glycolysis, mediates circadian control of carcinogenesis. In patients with tongue cancers, PFKFB3 expression in both cancers and its surrounding tissues was increased significantly compared with that in the control, and was accompanied with dys-regulated expression of core circadian genes. In the in vitro systems, SCC9 tongue cancer cells displayed rhythmic expression of PFKFB3 and CLOCK that was distinct from control KC cells. Furthermore, PFKFB3 expression in SCC9 cells was stimulated by CLOCK through binding and enhancing the transcription activity of PFKFB3 promoter. Inhibition of PFKFB3 at zeitgeber time 7 (ZT7), but not at ZT19 caused significant decreases in lactate production and in cell proliferation. Consistently, PFKFB3 inhibition in mice at circadian time (CT) 7, but not CT19 significantly reduced the growth of implanted neoplasms. Taken together, these findings demonstrate PFKFB3 as a mediator of circadian control of cancer growth, thereby highlighting the importance of time-based PFKFB3 inhibition in cancer treatment.