Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657.

中文翻译：

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聚梳信号和果糖-1、6-Bis磷酸酶之间的反馈电路可实现肝和肾肿瘤发生。

糖原异生的抑制增强了糖酵解，通常在源自糖原异生组织（包括肝脏和肾脏）的肿瘤中观察到，但是确定的调节机制仍然难以捉摸。在这里，我们筛选了一系列转录调节剂，并鉴定了zeste同源物2（EZH2）的增强子是抑制癌细胞糖异生的关键因素。具体来说，EZH2抑制限速的糖异生酶果糖-1、6-双磷酸酶1（FBP1）的表达，并主要通过抑制FBP1促进肿瘤的生长。此外，EZH2被通常诱导肝和肾肿瘤发生的基因毒素上调。基因毒素处理增强了EZH2的乙酰化作用，导致EZH2及其E3泛素连接酶SMURF2之间的缔合减少。因此，EZH2的泛素化程度降低了，变得更稳定了，促进FBP1衰减和肿瘤形成。有趣的是，FBP1与EZH2物理相互作用，竞争EZH2结合，并分解了多梳复合物。因此，FBP1抑制多梳启动的转录反应，并构成EZH2促进肿瘤发生必不可少的双负反馈环。最后，EZH2和FBP1水平在肿瘤组织中呈负相关，并能准确预测患者的存活率。这项工作揭示了表观遗传事件和代谢事件之间的意外相互作用，并确定了一个新的反馈电路，该电路突出了EZH2抑制剂作为肝癌和肾癌治疗剂。意义：涉及EZH2和抑制糖原异生酶FBP1的新型反馈环可促进肝细胞癌的生长。657。