Jie Yu1, Peiwei Chai1, Minyue Xie1, Shengfang Ge1, Jing Ruan1, Xianqun Fan1, Renbing Jia2. 1. Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China. 2. Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China. renbingjia@sjtu.edu.cn.
Abstract
BACKGROUND: Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. RESULTS: Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. CONCLUSION: We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.
BACKGROUND: Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. RESULTS: Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. CONCLUSION: We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.
Authors: Ricardo A Irizarry-Caro; Margaret M McDaniel; Garrett R Overcast; Viral G Jain; Ty Dale Troutman; Chandrashekhar Pasare Journal: Proc Natl Acad Sci U S A Date: 2020-11-16 Impact factor: 11.205
Authors: Di Zhang; Zhanyun Tang; He Huang; Guolin Zhou; Chang Cui; Yejing Weng; Wenchao Liu; Sunjoo Kim; Sangkyu Lee; Mathew Perez-Neut; Jun Ding; Daniel Czyz; Rong Hu; Zhen Ye; Maomao He; Y George Zheng; Howard A Shuman; Lunzhi Dai; Bing Ren; Robert G Roeder; Lev Becker; Yingming Zhao Journal: Nature Date: 2019-10-23 Impact factor: 49.962