NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma.

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.

Substrate stiffness affects neural network activity in an extracellular matrix proteins dependent manner.

Neuronal growth, differentiation, extension, branching and neural network activity are strongly influenced by the mechanical property of extracellular matrix (ECM). However, the mechanism by which substrate stiffness regulates a neural network activity, and the importance of ECM composition in conferring substrate stiffness sensing have not been explored. To address this question, the hippocampal neurons were seeded on the polydimethylsiloxane (PDMS) substrate with different stiffness, which were coated with fibronectin and laminin respectively. Our results show that voltage-gated Ca2+ channel currents are greater in neurons on the stiff substrate than on the soft substrate. In addition, the neurons exhibit a greater increase of Ca2+ currents on laminin-coated stiff substrate than on those coated with fibronectin, indicating that the composition of ECM can modulate responses to substrate stiffness of neurons. Paired patch-clamp recordings have shown that upregulation of neural effective synaptic connectivity is greater on the laminin-coated stiff substrate than on the fibronectin-coated ones. Consistently, laminin-coated stiff substrate enhances Ca2+ oscillations of neurons is greater that compared with the fibronectin-coated ones. Our study demonstrates that a direct role for substrate stiffness in regulating neuronal network activity and indicate that this modulation is dependent on a specific type of ECM protein, which should be taken into account for the design of biomaterials for neuronal tissue engineering.