編者按：1927年，德國(guó)醫(yī)生,、生理學(xué)家和生物化學(xué)家奧托·海因里?！ね郀柋ぃㄓ肿g沃伯格）正式提出著名的瓦氏效應(yīng)（沃伯格效應(yīng)）,，認(rèn)為癌細(xì)胞生長(zhǎng)速度遠(yuǎn)遠(yuǎn)大于正常細(xì)胞的原因來自能量來源差別,，癌細(xì)胞喜歡利用能量較低的葡萄糖（而非能量較高的脂肪酸）獲得能量,，并且喜歡通過效率較低的無氧發(fā)酵（而非效率較高的有氧呼吸）分解葡萄糖而釋放能量。如果切斷癌細(xì)胞的能量供應(yīng),，就有可能阻止癌細(xì)胞生長(zhǎng),。1931年,，瓦爾堡為此發(fā)現(xiàn)而被授予諾貝爾生理學(xué)醫(yī)學(xué)獎(jiǎng),。上百年來，該現(xiàn)象一直是癌癥研究的重要問題,。細(xì)胞能量代謝和轉(zhuǎn)錄程序的改變均為癌細(xì)胞特征之一,，可以使癌細(xì)胞持續(xù)快速增殖并轉(zhuǎn)移。不過,，控制癌細(xì)胞能量代謝重編程和轉(zhuǎn)錄調(diào)控之間相互作用的機(jī)制尚不明確,。

　　2018年4月3日，全球自然科學(xué)三大旗艦期刊之一,、英國(guó)《自然》正刊在線發(fā)表美國(guó)貝勒醫(yī)學(xué)院,、紐約羅斯韋爾·帕克綜合癌癥中心的研究報(bào)告，發(fā)現(xiàn)瓦氏效應(yīng)關(guān)鍵代謝酶——6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶4（PFKFB4）可以激活致癌類固醇受體輔助激活因子-3（SRC-3）對(duì)轉(zhuǎn)錄重編程進(jìn)行調(diào)節(jié)而引起乳腺癌,。

　　該研究通過全激酶組核糖核酸干擾篩選法,，確定了調(diào)節(jié)內(nèi)在SRC-3轉(zhuǎn)錄反應(yīng)的潛在激酶。瓦氏效應(yīng)葡萄糖發(fā)酵分解（糖酵解）刺激因子合成的有效調(diào)節(jié)酶——PFKFB4被發(fā)現(xiàn)是SRC-3的強(qiáng)刺激因子,，與雌激素受體有協(xié)同調(diào)節(jié)作用,。PFKFB4可以對(duì)SRC-3第857位絲氨酸（Ser857）進(jìn)行磷酸化，并且增強(qiáng)其轉(zhuǎn)錄活性,。因此,，抑制PFKFB4或第857位絲氨酸突變?yōu)楸彼幔⊿er857Ala）的磷酸化缺陷型SRC-3異位表達(dá)，可以消除SRC-3轉(zhuǎn)錄產(chǎn)物,。從功能而言,，PFKFB4所致SRC-3激活引起葡萄糖流向戊糖磷酸途徑（亦稱己糖磷酸旁路）并且通過轉(zhuǎn)錄上調(diào)轉(zhuǎn)酮酶（轉(zhuǎn)羥乙醛基酶）表達(dá)從而合成嘌呤。此外,，參與嘌呤代謝的兩種酶——單磷酸腺苷脫氨酶-1（AMPD1）和黃嘌呤脫氫酶（XDH）被確定為SRC-3靶蛋白,，可能直接或可能不直接參與嘌呤合成,。從機(jī)制而言，SRC-3的Ser857磷酸化通過保持SRC-3和ATF4向靶基因啟動(dòng)子集中,，加強(qiáng)其與轉(zhuǎn)錄因子ATF4的相互作用,。

　　于是，該研究通過SRC-3或PFKFB4抑制劑,，成功抑制了小鼠乳腺腫瘤生長(zhǎng),，并且防止了原發(fā)腫瘤向肺部轉(zhuǎn)移，Ser857Ala突變型SRC-3同樣如此,。PFKFB4和磷酸化SRC-3水平增加與雌激素受體陽性乳腺癌相關(guān),，而對(duì)于基底細(xì)胞樣三陰性乳腺癌亞型患者，PFKFB4和SRC-3所致常見蛋白質(zhì)表達(dá)譜與乳腺癌患者生存不良相關(guān),。

　　因此,，該研究結(jié)果表明，瓦氏效應(yīng)通路關(guān)鍵酶PFKFB4將糖代謝與轉(zhuǎn)錄激活進(jìn)行結(jié)合,，可以刺激SRC-3促使乳腺癌細(xì)胞的浸潤(rùn)和轉(zhuǎn)移,。該研究結(jié)果為乳腺癌的能量代謝靶向療法奠定了基礎(chǔ)。

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