Tumor-suppressive function of EZH2 is through inhibiting glutaminase.
Tumor-suppressive function of EZH2 is through inhibiting glutaminase.
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DOI：
10.1038/s41419-021-04212-7
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发表时间：
2021-10-20
影响因子：
9
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Liu Y;Tu CE;Guo X;Wu C;Gu C;Lai Q;Fang Y;Huang J;Wang Z;Li A;Liu S
肿瘤可以利用代谢重编程来抵御营养应激。表观遗传调节因子在代谢适应中发挥着关键作用。在这里，我们筛选了一个 sgRNA 文库，以确定导致结直肠癌 (CRC) 细胞对葡萄糖剥夺脆弱性的表观遗传调节因子，并发现更多 EZH2 敲除细胞在葡萄糖剥夺下存活下来。然后，我们发现，在葡萄糖敏感的 CRC 细胞系中，EZH2 表达因葡萄糖剥夺而显着下调，并且 EZH2 敲低细胞对葡萄糖剥夺具有更强的抵抗力。从机制上讲，EZH2缺陷上调谷氨酰胺酶（GLS）的表达并促进谷氨酸的产生，进而导致细胞内谷胱甘肽（GSH）的合成增加，并最终减弱由葡萄糖剥夺引起的活性氧（ROS）介导的细胞死亡。尽管 EZH2 在癌症进展中发挥癌基因的作用，并且 EZH2 敲除消除了小鼠模型中结直肠癌的发展，但在这里，我们通过直接调节 GLS 表达揭示了 EZH2 与代谢重编程之间的机制联系，并观察到结直肠癌组织中 EZH2 和 GLS 表达之间的负相关。这些发现进一步证实了异质性的重要性，从代谢角度为癌细胞对EZH2抑制剂的临床耐受性提供了解释，并提出了EZH2抑制剂与谷氨酰胺代谢抑制剂联合治疗癌症的可能性。
Tumors can use metabolic reprogramming to survive nutrient stress. Epigenetic regulators play a critical role in metabolic adaptation. Here we screened a sgRNA library to identify epigenetic regulators responsible for the vulnerability of colorectal cancer (CRC) cells to glucose deprivation and found that more EZH2-knockout cells survived glucose deprivation. Then, we showed that EZH2 expression was significantly downregulated in response to glucose deprivation in a glucose-sensitive CRC cell line, and EZH2-knockdown cells were more resistant to glucose deprivation. Mechanistically, EZH2 deficiency upregulated the expression of glutaminase (GLS) and promoted the production of glutamate, which in turn led to increased synthesis of intracellular glutathione (GSH) and eventually attenuated the reactive oxygen species (ROS)-mediated cell death induced by glucose deprivation. Although EZH2 functioned as an oncogene in cancer progression and EZH2 knockout abolished colorectal cancer development in a mouse model, here we revealed a mechanistic link between EZH2 and metabolic reprogramming via the direct regulation of GLS expression and observed a negative correlation between EZH2 and GLS expression in colorectal cancer tissues. These findings further confirmed the importance of heterogeneity, provided an explanation for the clinical tolerance of cancer cells to EZH2 inhibitors from the perspective of metabolism, and proposed the possibility of combining EZH2 inhibitors and glutamine metabolism inhibitors for the treatment of cancer.
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影响因子：
29
作者：
Lee JV;Carrer A;Shah S;Snyder NW;Wei S;Venneti S;Worth AJ;Yuan ZF;Lim HW;Liu S;Jackson E;Aiello NM;Haas NB;Rebbeck TR;Judkins A;Won KJ;Chodosh LA;Garcia BA;Stanger BZ;Feldman MD;Blair IA;Wellen KE
通讯作者：
Wellen KE
衰老会减少 ERRα 引导的线粒体谷氨酰胺酶表达，从而抑制谷氨酰胺回补和间充质干细胞的成骨分化。
影响因子：
5.2
作者：
Huang, Tongling;Liu, Renzhong;Guan, Min
通讯作者：
Guan, Min
DOI：
10.1073/pnas.1700909114
发表时间：
2017-05-09
影响因子：
11.1
作者：
Liu, Yongfeng;Peng, Junjie;Qin, Jun
通讯作者：
Qin, Jun
影响因子：
4.8
作者：
Madison, BB;Dunbar, L;Gumucio, DL
通讯作者：
Gumucio, DL
影响因子：
6.4
作者：
Alhopuro, Pia;Sammalkorpi, Heli;Aaltonen, Lauri A.
通讯作者：
Aaltonen, Lauri A.