Journal Article

High Sugar Induced RCC2 Lactylation Drives Breast Cancer Tumorigenicity Through Upregulating MAD2L1

Zhou, Baian, Ye, Danrong, Zhong, Seng, Yu, Bolin, Zheng, Bowen, Pan, Yunhao, Qian, Fengyuan, Liu, Diya, Zheng, Wenfang, Wang, Yuying, Fang, Lin, Wang, Xuehui

2025

Overview

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. This study finds that KAT2A mediates the lactylation modification of the non‐histone protein RCC2 at K124, facilitating the recruitment of free SERBP1 and aiding in the formation of the initial SERBP1‐MAD2L1 complex. SERBP1 enhances the stability of MAD2L1 mRNA and promotes cellular proliferation. Targeting RCC2 lactylation to restrict the rapid proliferation of breast cancer represents a novel proof‐of‐concept strategy.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Acids / Animals / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell division / Cell growth / Cell Line, Tumor / Cell Proliferation / Chemotherapy / Chromosomes / Female / Gene Expression Regulation, Neoplastic / Glucose / high sugar diet / Humans / Mad2 Proteins - genetics / Mad2 Proteins - metabolism / MAD2L1 / Medical prognosis / Metabolism / Metastasis / Mice / Protein Processing, Post-Translational / Proteins / RCC2 / SERBP1 / Tumors / Up-Regulation