NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma
NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma
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NeuroD1通过直接激活结直肠癌中磷酸戊糖途径促进肿瘤细胞增殖和肿瘤发生
DOI：
10.1038/s41388-021-02063-2
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发表时间：
2021-10-16
期刊：
影响因子：
8
通讯作者：
Kasim, Vivi
中科院分区：
文献类型：
--
作者：
Li, Zhuolin;He, Yuxin;Kasim, Vivi
肿瘤代谢重编程确保癌细胞获得足够的构建模块、能量和抗氧化剂以维持快速生长和应对氧化应激。神经源性分化因子1（NeuroD 1）在各种类型的肿瘤中上调;然而，其参与肿瘤细胞代谢重编程仍不清楚。在这项研究中，我们报告了NeuroD 1与结直肠癌细胞中戊糖磷酸途径（PPP）中的限速酶葡萄糖-6-磷酸脱氢酶（G6 PD）正相关。此外，NeuroD 1对G6 PD的调节通过刺激PPP改变肿瘤细胞代谢，导致核苷酸和NADPH的产生增加。这些反过来又促进肿瘤细胞中DNA和脂质的生物合成，同时降低细胞内活性氧的水平。从机制上讲，我们表明NeuroD 1直接结合G6 PD启动子，激活G6 PD转录。因此，肿瘤细胞增殖和集落形成增强，导致体外和体内致瘤潜力增加。这些发现揭示了NeuroD 1作为G6 PD调节剂的新功能，其致癌活性与肿瘤细胞代谢重编程和PPP调节有关。此外，NeuroD 1代表了基于代谢的抗肿瘤治疗策略的潜在靶点。
Tumor metabolic reprogramming ensures that cancerous cells obtain sufficient building blocks, energy, and antioxidants to sustain rapid growth and for coping with oxidative stress. Neurogenic differentiation factor 1 (NeuroD1) is upregulated in various types of tumors; however, its involvement in tumor cell metabolic reprogramming remains unclear. In this study, we report that NeuroD1 is positively correlated with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP), in colorectal cancer cells. In addition, the regulation of G6PD by NeuroD1 alters tumor cell metabolism by stimulating the PPP, leading to enhanced production of nucleotides and NADPH. These, in turn, promote DNA and lipid biosynthesis in tumor cells, while decreasing intracellular levels of reactive oxygen species. Mechanistically, we showed that NeuroD1 binds directly to the G6PD promoter to activate G6PD transcription. Consequently, tumor cell proliferation and colony formation are enhanced, leading to increased tumorigenic potential in vitro and in vivo. These findings reveal a novel function of NeuroD1 as a regulator of G6PD, whereby its oncogenic activity is linked to tumor cell metabolic reprogramming and regulation of the PPP. Furthermore, NeuroD1 represents a potential target for metabolism-based anti-tumor therapeutic strategies.