Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
Oncogene. 2021 Dec;40(50):6736-6747. doi: 10.1038/s41388-021-02063-2. Epub 2021 Oct 16.
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.
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，以维持快速生长并应对氧化应激。神经源性分化因子 1（NeuroD1）在各种类型的肿瘤中上调；然而，其在肿瘤细胞代谢重编程中的作用尚不清楚。在这项研究中，我们报告神经源性分化因子 1与葡萄糖-6-磷酸脱氢酶（G6PD）呈正相关，葡萄糖-6-磷酸脱氢酶是戊糖磷酸途径（PPP）中的限速酶，在结直肠癌细胞中也是如此。此外，NeuroD1 对 G6PD 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。反过来，这促进了肿瘤细胞的 DNA 和脂质生物合成，同时降低了细胞内活性氧的水平。在机制上，我们表明神经源性分化因子 1直接结合 G6PD 启动子以激活 G6PD 转录。因此，肿瘤细胞的增殖和集落形成增强，导致体外和体内肿瘤发生潜力增加。这些发现揭示了神经源性分化因子 1作为 G6PD 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，神经源性分化因子 1代表了基于代谢的抗肿瘤治疗策略的潜在靶点。
