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 

机构地区：[1]Cancer Research Center,Beijing Chest Hospital,Capital Medical University,Beijing Tuberculosis and Thoracic Tumor Institute,Beijing 101149,China [2]College of Life Sciences&Bioengineering,Beijing Jiaotong University,Beijing 100044,China [3]Department of Endoscopic Diagnosis and Treatment,Beijing Chest Hospital,Capital Medical University,Beijing Tuberculosis and Thoracic Tumor Institute,Beijing 101149,China [4]CAS Key Laboratory of Computational Biology,Shanghai Institute of Nutrition and Health,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第5期2086-2106,共21页药学学报（英文版）

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。

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 development.Here,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 genes.We identified an intragenic CpG island(iCpGI)in PRSS3.Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1(MZF1)to regulate PRSS3 transcription.The 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 expression.Epigenetic 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 disease.Thus,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.

关 键 词：Lung cancer Intratumor heterogeneity Splice variants Intragenic CpG methylation Protease serine 3 Myeloid zinc finger 1 UHRF1/DNMT1 5-AZA-CDR 

分 类 号：R734.2[医药卫生—肿瘤]