Zheng Bowen, Pan Yunhao, Qian Fengyuan, Liu Diya, Ye Danrong, Yu Bolin, Zhong Seng, Zheng Wenfang, Wang Xuehui, Zhou Baian, Wang Yuying, Fang Lin
Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200070, China.
Department of Breast Surgery, Shanghai Second People's Hospital, Shanghai, 200011, China.
Adv Sci (Weinh). 2025 Jun;12(21):e2415530. doi: 10.1002/advs.202415530. Epub 2025 Mar 27.
Lactylation is a novel post-translational modification mediated by lactate, widely present in the lysine residues of both histone and non-histone proteins. However, the specific regulatory mechanisms and downstream target proteins remain unclear. Herein, it is demonstrated that the RCC2 protein may serve as a critical link between material metabolism and cell division, promoting the rapid proliferation of breast cancer under high glucose conditions. Mechanistically, the activation of glycolysis leads to an increase in lactate. Then, acyltransferase KAT2A mediates RCC2 lactylation at K124, which assists RCC2 in recruiting free SERBP1, thereby stabilizing MAD2L1 mRNA. The lactylation of RCC2 mediates the activation of the cellular MAD2L1 signaling pathway and contributes to the progression of breast cancer. A small molecule inhibitor slows down cell proliferation by binding to the RCC2 active pocket and specifically blocking RCC2 lactylation. The findings elucidate the mechanism behind the upregulation of MAD2L1 in murine tumors associated with a high-sugar diet as reported in prior study and suggest a novel therapeutic strategy of targeting RCC2 lactylation to restrict the rapid proliferation of breast cancer cell in a high-lactate microenvironment.
乳酰化是一种由乳酸介导的新型翻译后修饰，广泛存在于组蛋白和非组蛋白的赖氨酸残基中。然而，其具体调控机制和下游靶蛋白仍不清楚。本文证明，RCC2蛋白可能是物质代谢与细胞分裂之间的关键纽带，在高糖条件下促进乳腺癌的快速增殖。机制上，糖酵解的激活导致乳酸增加。然后，酰基转移酶KAT2A介导RCC2在K124位点的乳酰化，这有助于RCC2招募游离的SERBP1，从而稳定MAD2L1 mRNA。RCC2的乳酰化介导细胞MAD2L1信号通路的激活，并促进乳腺癌的进展。一种小分子抑制剂通过与RCC2活性口袋结合并特异性阻断RCC2乳酰化来减缓细胞增殖。这些发现阐明了先前研究中报道的高糖饮食相关小鼠肿瘤中MAD2L1上调背后的机制，并提出了一种靶向RCC2乳酰化以限制高乳酸微环境中乳腺癌细胞快速增殖的新型治疗策略。
