LSH-p53-PRODH生物轴通过脯氨酸代谢调节炎症因子的研究

Proline metabolism is closely related to apoptosis, autophagy and senescence during tumor progression. However, it is unclear whether proline metabolism affects the malignant transformation of inflammation. Epigenetic modification, characterized by chromatin remodeling, has become a new key information integration interface for the study of cancer metabolic reprogramming. This project will set chromatin remodeling protein LSH as the key node and metabolic related enzyme PRODH/POX as a potential target. It is proposed that LSH may upregulate p53 via ubiquitin-proteasome pathway and activate PRODH. LSH may also replenish α-KG, maintains PRODH activity and generates ATP through proline cycle, thereby regulating the expression of inflammatory factors such as IL-17C and CXCL1 mediated by nuclear IKK alpha, and promoting the malignant transformation of inflammation to cancer. In this project, we will explore innovatively the dynamic integration mechanism of LSH-p53-PRODH axis regulating inflammatory factors on malignant transformation and metabolic reprogramming, providing new clues and theoretical basis for prevention and treatment of malignant tumor.

脯氨酸代谢与肿瘤进程中的凋亡、自噬、衰老等密切相关，然而脯氨酸代谢是否影响炎症恶性转化尚不清楚。以染色质重塑为特点的表观遗传修饰已成为研究肿瘤代谢重编程新的关键信息整合接口。本项目将以染色质重塑蛋白LSH 为关键节点，以代谢相关酶 PRODH/POX 调节炎症因子为靶点，拟研究LSH可能通过泛素-蛋白酶体途径上调 p53 ，从而活化 PRODH。LSH 也可能通过脯氨酸循环回补 α-KG，维持 PRODH 的活性和产生 ATP 提供能量，进而调节核 IKKα 介导的 IL-17C、CXCL1 等炎症因子表达，促进炎症向肿瘤的恶性转化。本项目通过开展转录调控和代谢重编程的交互研究，创新性的探讨LSH-p53-PRODH生物轴调节炎症因子对细胞恶性转化、代谢重编程之间的动态整合机制，为恶性肿瘤的防治提供新的线索和理论依据。

代谢失调与肿瘤的发生发展密切相关，然而这些代谢途径中的关键驱动因素尚不清楚。本项目我们探讨了脯氨酸分解代谢在非小细胞肺癌（NSCLC）中的关键作用，染色质重塑因子淋巴特异性解旋酶（LSH）是NSCLC的表观遗传驱动因素，我们发现脯氨酸脱氢酶（PRODH）被LSH激活以降低脯氨酸水平，PRODH依赖于脯氨酸分解代谢促进NSCLC的细胞增殖、克隆形成、迁移与侵袭以及裸鼠移植瘤的生长。此外，PRODH通过产生ROS促进IKKα的磷酸化，激活IKKα对炎症因子CXCL1、LCN2和IL17C的转录调控。本项目通过开展转录调控和代谢重编程的交互研究，创新性的探索LSH-p53-PRODH生物轴调节炎症因子对细胞恶性转化、代谢重编程之间的动态整合机制，为恶性肿瘤的防治提供新的线索和理论依据。