A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis
A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis
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DOI：
10.1158/0008-5472.can-19-2060
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发表时间：
2020-02-15
期刊：
影响因子：
11.2
通讯作者：
Li, Bo
中科院分区：
文献类型：
--
作者：
Liao, Kun;Deng, Shuye;Li, Bo
糖异生抑制可促进糖酵解，这在肝、肾等糖异生组织衍生的肿瘤中普遍存在，但其明确的调节机制尚不明确。在这里，我们筛选了一系列转录调节因子，并确定了zeste同源物2的增强子（EZH2）是抑制癌细胞糖异生的关键因子。具体来说，EZH2抑制了限制性糖异生酶果糖- 1,6 -二磷酸酶1 （FBP1）的表达，并主要通过抑制FBP1促进肿瘤生长。此外，EZH2被通常诱导肝脏和肾脏肿瘤发生的基因毒素上调。基因毒素处理增强EZH2乙酰化，导致EZH2与其E3泛素连接酶SMURF2之间的关联降低。因此，EZH2泛素化程度降低，更加稳定，促进fbp1的减弱和肿瘤的形成。有趣的是，FBP1与EZH2发生物理相互作用，竞争EZH2的结合，并使多梳复合物脱落。因此，FBP1抑制polycomb启动的转录反应，并构成ezh2促进肿瘤发生不可或缺的双负反馈回路。最后，EZH2和FBP1水平在肿瘤组织中呈负相关，可以准确预测患者的生存。这项工作揭示了表观遗传和代谢事件之间意想不到的串扰，并确定了一个新的反馈回路，突出了EZH2抑制剂作为肝癌和肾癌的治疗方法。意义：一个涉及EZH2和抑制糖异生酶FBP1的新的反馈回路促进肝细胞癌的生长。
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, promotingFBP1 attenuationandtumor formation. Intrigu- ingly, 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.