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

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2086-2106页

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 Cancer Research Center Beijing Chest HospitalCapital Medical UniversityBeijing Tuberculosis and Thoracic Tumor InstituteBeijing 101149China College of Life Sciences&Bioengineering Beijing Jiaotong UniversityBeijing 100044China Department of Endoscopic Diagnosis and Treatment Beijing Chest HospitalCapital Medical UniversityBeijing Tuberculosis and Thoracic Tumor InstituteBeijing 101149China CAS Key Laboratory of Computational Biology Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China

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.

关键词： Lung cancer Intratumor heterogeneity Splice variants Intragenic CpG methylation protease serine 3 Myeloid zinc finger 1 UHRF1/DNMT1 5-Aza-CdR

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