Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1
Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1
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Lin28/let-7 轴通过 PDK1 调节有氧糖酵解和癌症进展
DOI：
10.1038/ncomms6212
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发表时间：
2014-10-01
影响因子：
16.6
通讯作者：
Zhang, Huafeng
中科院分区：
文献类型：
--
作者：
Ma, Xiaoyu;Li, Chenchen;Zhang, Huafeng
Lin 28和let-7的异常表达已在许多人类恶性肿瘤中观察到。然而，其职能和基本机制在很大程度上仍然难以捉摸。在这里，我们表明，Lin 28和let-7的异常表达促进有氧糖酵解，或瓦尔堡效应，在癌细胞中。从机制上讲，我们发现Lin 28 A和Lin 28 B以缺氧或缺氧诱导因子-1（HIF-1）非依赖性方式通过靶向丙酮酸脱氢酶激酶1（PDK 1）增强有氧糖酵解，而let-7则抑制有氧糖酵解，这说明了即使在环境氧气水平下也能介导癌细胞有氧糖酵解的新途径。更重要的是，我们进一步证实了PDK 1在体外和体内对Lin 28 A和Lin 28 B介导的肿瘤增殖都是至关重要的，建立了一种以前未被认识的机制，通过该机制Lin 28/let-7轴促进瓦尔堡效应以促进癌症进展。我们的研究结果表明，在Lin 28和let-7异常表达的恶性肿瘤中靶向PDK 1用于癌症治疗的潜在原理。
Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we discover that Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1, in a hypoxia- or hypoxia-inducible factor-1 (HIF-1)-independent manner, illustrating a novel pathway to mediate aerobic glycolysis of cancer cells even in ambient oxygen levels. Importantly, we further demonstrate that PDK1 is critical for Lin28A- and Lin28B-mediated cancer proliferation bothin vitroandin vivo, establishing a previously unappreciated mechanism by which Lin28/let-7 axis facilitates Warburg effect to promote cancer progression. Our findings suggest a potential rationale to target PDK1 for cancer therapy in malignancies with aberrant expression of Lin28 and let-7.