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编者按：1927年，德国医生、生理学家和生物化学家奥托·海因里希·瓦尔堡（又译沃伯格）正式提出著名的瓦氏效应（沃伯格效应），认为癌细胞生长速度远远大于正常细胞的原因来自能量来源差别，癌细胞喜欢利用能量较低的葡萄糖（而非能量较高的脂肪酸）获得能量，并且喜欢通过效率较低的无氧发酵（而非效率较高的有氧呼吸）分解葡萄糖而释放能量。如果切断癌细胞的能量供应，就有可能阻止癌细胞生长。1931年，瓦尔堡为此发现而被授予诺贝尔生理学医学奖。上百年来，该现象一直是癌症研究的重要问题。细胞能量代谢和转录程序的改变均为癌细胞特征之一，可以使癌细胞持续快速增殖并转移。不过，控制癌细胞能量代谢重编程和转录调控之间相互作用的机制尚不明确。 2018年4月3日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国贝勒医学院、纽约罗斯韦尔·帕克综合癌症中心的研究报告，发现瓦氏效应关键代谢酶——6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶4（PFKFB4）可以激活致癌类固醇受体辅助激活因子-3（SRC-3）对转录重编程进行调节而引起乳腺癌。 该研究通过全激酶组核糖核酸干扰筛选法，确定了调节内在SRC-3转录反应的潜在激酶。瓦氏效应葡萄糖发酵分解（糖酵解）刺激因子合成的有效调节酶——PFKFB4被发现是SRC-3的强刺激因子，与雌激素受体有协同调节作用。PFKFB4可以对SRC-3第857位丝氨酸（Ser857）进行磷酸化，并且增强其转录活性。因此，抑制PFKFB4或第857位丝氨酸突变为丙氨酸（Ser857Ala）的磷酸化缺陷型SRC-3异位表达，可以消除SRC-3转录产物。从功能而言，PFKFB4所致SRC-3激活引起葡萄糖流向戊糖磷酸途径（亦称己糖磷酸旁路）并且通过转录上调转酮酶（转羟乙醛基酶）表达从而合成嘌呤。此外，参与嘌呤代谢的两种酶——单磷酸腺苷脱氨酶-1（AMPD1）和黄嘌呤脱氢酶（XDH）被确定为SRC-3靶蛋白，可能直接或可能不直接参与嘌呤合成。从机制而言，SRC-3的Ser857磷酸化通过保持SRC-3和ATF4向靶基因启动子集中，加强其与转录因子ATF4的相互作用。 于是，该研究通过SRC-3或PFKFB4抑制剂，成功抑制了小鼠乳腺肿瘤生长，并且防止了原发肿瘤向肺部转移，Ser857Ala突变型SRC-3同样如此。PFKFB4和磷酸化SRC-3水平增加与雌激素受体阳性乳腺癌相关，而对于基底细胞样三阴性乳腺癌亚型患者，PFKFB4和SRC-3所致常见蛋白质表达谱与乳腺癌患者生存不良相关。 因此，该研究结果表明，瓦氏效应通路关键酶PFKFB4将糖代谢与转录激活进行结合，可以刺激SRC-3促使乳腺癌细胞的浸润和转移。该研究结果为乳腺癌的能量代谢靶向疗法奠定了基础。 Nature. 2018 Apr 3. [Epub ahead of print] Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Subhamoy Dasgupta, Kimal Rajapakshe, Bokai Zhu, Bryan C. Nikolai, Ping Yi, Nagireddy Putluri, Jong Min Choi, Sung Y. Jung, Cristian Coarfa, Thomas F. Westbrook, Xiang H.-F. Zhang, Charles E. Foulds, Sophia Y. Tsai, Ming-Jer Tsai, Bert W. O'Malley. Baylor College of Medicine, Houston, TX, USA; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis. However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis, is found to be a robust stimulator of SRC-3 that coregulates oestrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC-3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in oestrogen receptor-positive tumours, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumours. DOI: 10.1038/s41586-018-0018-1
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