Duan Yimeng, Li Peixian, Yang Yanmei, Wu Guanghua, Xing Hao, Chen Hong, Zhao Liangbo, Liu Lei, Sun Xiao, Jin Shuiling, He Luyun, Liu Benyu
State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
Cell Death Dis. 2025 Aug 10;16(1):605. doi: 10.1038/s41419-025-07929-x.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, characterized by molecular heterogeneity and limited therapeutic options. Here, we identified EPS8L2 as a novel driver of colorectal tumorigenesis. EPS8L2 is significantly upregulated in CRC tissues and negatively correlated with patients' prognosis. Functionally, upregulation of EPS8L2 promotes proliferation and metastasis of CRC cells in vitro and in vivo, and vice versa. Similarly, EPS8L2 overexpression promotes patient-derived organoids growth. Mechanistically, EPS8L2 increases YBX1 phosphorylation by enhancing its interaction with phosphokinase S6K1. Phosphorylated YBX1 translocates into nucleus and initiates G3BP2 transcription, leading to activation of the MAPK signaling pathway. Moreover, knockout of Eps8l2 impairs CRC tumorigenesis in the AOM/DSS induced mouse model. In summary, we revealed a novel EPS8L2-YBX1-G3BP2 regulatory axis involved in CRC progression, which provides a new theoretical basis for tumor therapy.
结直肠癌（CRC）仍是全球癌症相关死亡的主要原因，其特征是分子异质性和治疗选择有限。在此，我们将EPS8L2鉴定为结直肠肿瘤发生的一种新型驱动因子。EPS8L2在CRC组织中显著上调，且与患者预后呈负相关。在功能上，EPS8L2的上调促进CRC细胞在体外和体内的增殖与转移，反之亦然。同样，EPS8L2的过表达促进患者来源类器官的生长。机制上，EPS8L2通过增强其与磷酸激酶S6K1的相互作用来增加YBX1的磷酸化。磷酸化的YBX1易位至细胞核并启动G3BP2转录，导致MAPK信号通路的激活。此外，在AOM/DSS诱导的小鼠模型中，Eps8l2的敲除损害了结直肠癌的发生。总之，我们揭示了一条参与CRC进展的新型EPS8L2 - YBX1 - G3BP2调控轴，这为肿瘤治疗提供了新的理论基础。
