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

• DOI: 10.1002/advs.202415530
• Publication Date: 2025-03-30T08:53:53Z
• Authors: Bowen Zheng; Yunhao Pan; Fengyuan Qian; Diya Liu; Danrong Ye; Bolin Yu; Seng Zhong; Wenfang Zheng; Xuehui Wang; Baian Zhou; Yuying Wang; Lin Fang

Abstract Lactylation is a novel post‐translational modification mediated by lactate, widely present in the lysine residues of both histone and non‐histone proteins. However, specific regulatory mechanisms downstream target proteins remain unclear. Herein, it demonstrated that RCC2 protein may serve as critical link between material metabolism cell division, promoting rapid proliferation breast cancer under high glucose conditions. Mechanistically, activation glycolysis leads to an increase lactate. Then, acyltransferase KAT2A mediates lactylation at K124, which assists recruiting free SERBP1, thereby stabilizing MAD2L1 mRNA. The cellular signaling pathway contributes progression cancer. A small molecule inhibitor slows down binding active pocket specifically blocking lactylation. findings elucidate mechanism behind upregulation murine tumors associated with high‐sugar diet reported prior study suggest therapeutic strategy targeting restrict high‐lactate microenvironment.