UHRF1/DNMT1—MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer

作     者：Shuye Lin Hanli Xu Lin Qin Mengdi Pang Ziyu Wang Meng Gu Lishu Zhang Cong Zhao Xuefeng Hao Zhiyun Zhang Weimin Ding Jianke Ren Jiaqiang Huang Shuye Lin;Hanli Xu;Lin Qin;Mengdi Pang;Ziyu Wang;Meng Gu;Lishu Zhang;Cong Zhao;Xuefeng Hao;Zhiyun Zhang;Weimin Ding;Jianke Ren;Jiaqiang Huang

作者机构：Cancer Research CenterBeijing Chest HospitalCapital Medical UniversityBeijing Tuberculosis and Thoracic Tumor InstituteBeijing 101149China College of Life Sciences&BioengineeringBeijing Jiaotong UniversityBeijing 100044China Department of Endoscopic Diagnosis and TreatmentBeijing Chest HospitalCapital Medical UniversityBeijing Tuberculosis and Thoracic Tumor InstituteBeijing 101149China CAS Key Laboratory of Computational BiologyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第5期

页      面：2086-2106页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：National Natural Science Foundation of China(NSFC grant No.32200462,China) National Natural Science Foundation of China(NSFC grant No.81872021,China) Beijing Municipal Administration of Hospitals Youth Program(grant No.QMS20221603,China) R&D Program of Beijing Municipal Education Commission(grant No.KM202110025004,China) Beijing Natural Science Foundation of China(BJSFC No.7214242,China) Beijing Municipal Administration of Hospitals Incubating Program(grant No.PX2021063,China) Intramural Research Funding Program from Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital 

主　　题：Lung cancer Intratumor heterogeneity Splice variants Intragenic CpG methylation Protease serine 3 Myeloid zinc finger 1 UHRF1/DNMT1 5-Aza-CdR 

摘      要：As confusion mounts over RNA isoforms involved in phenotypic plasticity,aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity(ITH).Protease serine 3(PRSS3),possessing four splice variants(PRSS3-SVs;PRSS3-V1—V4),is an indispensable trypsin that shows paradoxical effects on cancer ***,we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer,exhibiting opposing functions and clinical outcomes,namely,oncogenic PRSS3-V1 and PRSS3-V2 versus tumorsuppressive PRSS3-V3,by targeting different downstream *** identified an intragenic CpG island(iCpGI)in *** of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1(MZF1)to regulate PRSS3 *** garlic-derived compound diallyl trisulfide cooperated with 5-aza-2 -deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 *** silencing of PRSS3-V3 via i CpGI methylation(iCpGIm)in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory ***,UHRF1/DNMT1—MZF1 axismodulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs,conferring nongenetic functional ITH,with implications for early detection of lung cancer and targeted therapies.