H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.
H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.
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DOI：
10.1038/s41388-022-02283-0
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发表时间：
2022-04
期刊：
影响因子：
8
通讯作者：
Liu, Kebin
中科院分区：
文献类型：
--
作者：
Lu, Chunwan;Yang, Dafeng;Klement, John D.;Colson, Yolonda L.;Oberlies, Nicholas H.;Pearce, Cedric J.;Colby, Aaron H.;Grinstaff, Mark W.;Liu, Zhuoqi;Shi, Huidong;Ding, Han-Fei;Liu, Kebin
葡萄糖-6-磷酸脱氢酶（G6 PD）在人类癌症中的作用还不完全清楚。在代谢物筛选中，我们观察到H3 K9甲基化的抑制抑制人间皮瘤细胞中的有氧糖酵解并增强PPP。全基因组筛选鉴定G6 PD为H3 K9 me 3靶基因，其表达与增加的肿瘤细胞凋亡相关。抑制有氧糖酵解酶LDHA和G6 PD对肿瘤细胞存活没有显著影响。G6 PD的消融对无胸腺小鼠中的人间皮瘤和结肠癌异种移植物生长没有显著影响。然而，用G6 PD选择性激活剂AG 1激活G6 PD诱导肿瘤细胞死亡。AG 1增加了肿瘤细胞ROS的产生以及由此产生的肿瘤细胞中的外在和内在死亡途径、线粒体过程和未折叠蛋白反应。与体外增加的肿瘤细胞死亡一致，AG 1在体内以剂量依赖性方式抑制人间皮瘤异种移植物生长。此外，在腹膜内异种移植无胸腺小鼠模型中，AG 1治疗显著增加了荷瘤小鼠的存活率。因此，在人类间皮瘤和结肠癌中，G6 PD对于肿瘤生长不是必需的。G6 PD作为一个代谢检查点，控制代谢流向PPP，促进肿瘤细胞凋亡，其表达受到其启动子H3 K9 me 3沉积的抑制。
The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathway, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition.
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影响因子：
20.8
作者：
Chen, Li;Zhang, Zhaoyue;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.
影响因子：
13.6
作者：
Ding H;Chen Z;Wu K;Huang SM;Wu WL;LeBoeuf SE;Pillai RG;Rabinowitz JD;Papagiannakopoulos T
通讯作者：
Papagiannakopoulos T
影响因子：
16.6
作者：
Hwang S;Mruk K;Rahighi S;Raub AG;Chen CH;Dorn LE;Horikoshi N;Wakatsuki S;Chen JK;Mochly-Rosen D
通讯作者：
Mochly-Rosen D
影响因子：
3.4
作者：
Amrine CSM;Raja HA;Darveaux BA;Pearce CJ;Oberlies NH
通讯作者：
Oberlies NH
影响因子：
64.8
作者：
Lachner, M;O'Carroll, N;Jenuwein, T
通讯作者：
Jenuwein, T