ZC3H18的相分离转录激活LDHA并形成乳酸化介导的正反馈环路以促进肺癌发生
The phase separation of ZC3H18 transcriptionally activates LDHA and forms lactylation-mediated positive feedback loop to promote tumorigenesis of lung cancer.
作者
作者单位
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China.
- Department of Public Health, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China. changzhang2525@163.com.
- Central Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Department of Respiratory Medicine, Zhongda Hospital of Southeast University, Nanjing, China.
- Department of Radiotherapy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. luxiyi@njmu.edu.cn.
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China. pingpingwu_njmu@163.com.
- Department of Oncology, Xuzhou Central Hospital, Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, China. hanliang_njmu@sina.com.
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. erbaozhang@njmu.edu.cn.
摘要
中文
RNA结合蛋白（RBPs）在肿瘤发生及癌症治疗中发挥关键作用。鉴于代谢重编程参与肿瘤发生，阐明RBPs与代谢之间的相互作用机制可为肿瘤生物学提供新见解。本研究发现RBP ZC3H18在肺癌中通过拷贝数增加而过表达，发挥促癌功能。机制上，ZC3H18发生相分离，通过结合LDHA启动子转录激活关键代谢酶乳酸脱氢酶A（LDHA），从而促进糖酵解及乳酸生成。乳酸的积累又可通过组蛋白H3K18乳酸化（H3K18la）激活ZC3H18的转录，并在翻译后水平直接诱导ZC3H18 Lys186位点（K186）的乳酸化，从而形成ZC3H18/LDHA/乳酸/ZC3H18正反馈环路。此外，在肺癌患者来源的异种移植（PDX）模型中，ZC3H18抑制联合LDHA小分子抑制剂（GSK2837808A）表现出更好的抗肿瘤效果，提示靶向ZC3H18/LDHA轴的治疗潜力。综上，本研究从新颖的角度阐明了RBP相分离与乳酸代谢之间的对话机制，并提示ZC3H18/LDHA轴可能是肺癌的潜在治疗靶点。
English
RNA-binding proteins (RBPs) play crucial roles in tumorigenesis and cancer treatment. As metabolic reprogramming is known to participate in tumorigenesis, elucidation of the mechanisms of crosstalk between RBPs and metabolism could provide new insights into cancer biology. Here, we found that the RBP ZC3H18 is overexpressed in lung cancer through copy number gain, which exerts oncogenic functions. Mechanistically, ZC3H18 undergoes phase separation to transcriptionally activate a key metabolic enzyme, lactate dehydrogenase A (LDHA), by binding to the LDHA promoter, thus promoting glycolysis and the production of lactate. The accumulation of lactate, in turn, activates the transcription of ZC3H18 through histone H3K18 lactylation (H3K18la) and directly induces the lactylation of ZC3H18 at the Lys186 residue (K186) in post-translational, thus forming a positive ZC3H18/LDHA/lactate/ZC3H18 feedback loop. Moreover, the combination of ZC3H18 inhibition and an LDHA small-molecule inhibitor (GSK2837808A) exhibited better antitumor efficacy in lung cancer patient-derived xenograft (PDX) model, suggesting the therapeutic potential of targeting the ZC3H18/LDHA axis. Taken together, our findings clarify the dialogue between RBP phase separation and lactate metabolism from a novel perspective and suggest that the ZC3H18/LDHA axis may serve as a potential therapeutic target for lung cancer.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 9.1
- 新锐分区
- 1区