PMID- 32089740 OWN - NLM STAT- MEDLINE DCOM- 20210414 LR - 20210414 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 10 IP - 5 DP - 2020 TI - 19q13 KRAB zinc-finger protein ZNF471 activates MAPK10/JNK3 signaling but is frequently silenced by promoter CpG methylation in esophageal cancer. PG - 2243-2259 LID - 10.7150/thno.35861 [doi] AB - Zinc-finger proteins (ZFPs) are the largest transcription factor family in mammals, involved in the regulation of multiple physiologic processes including cell differentiation, proliferation, apoptosis and neoplastic transformation. Approximately one-third of ZFPs are Kruppel-associated box domain (KRAB)-ZFPs. Methods: ZNF471 expression and methylation were detected by reverse-transcription PCR and methylation-specific PCR. The impact and mechanism of ectopic ZNF471 expression in esophageal squamous cell carcinoma (ESCC) cells was evaluated in vitro and in vivo. Results: We identified a 19q13 KRAB-ZFP, ZNF471, as a methylated target in ESCC. We further found that ZNF471 is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues, due to its aberrant promoter CpG methylation, and further confirmed by methylation analysis and treatment with demethylation agent. Restoration of ZNF471 expression in silenced ESCC cells significantly altered cell morphology, induced apoptosis and G0/G1 arrest, and inhibited tumor cell colony formation, viability, migration and invasion. Importantly, ZNF471 was found to activate the expression of MAPK10/JNK3 and PCDH family genes, and further enhance MAPK10 signaling and downstream gene expression through binding to the MAPK10/JNK3 promoter. Conclusion: Our results demonstrate that ZNF471 is an important tumor suppressor and loss of ZNF471 functions hampers MAPK10/JNK3 signaling during esophageal carcinogenesis. CI - (c) The author(s). FAU - Sun, Ran AU - Sun R AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Xiang, Tingxiu AU - Xiang T AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Tang, Jun AU - Tang J AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Peng, Weiyan AU - Peng W AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Luo, Jie AU - Luo J AD - Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK-Shenzhen Research Institute, Hong Kong. FAU - Li, Lili AU - Li L AD - Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK-Shenzhen Research Institute, Hong Kong. FAU - Qiu, Zhu AU - Qiu Z AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Tan, Yiqing AU - Tan Y AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Ye, Lin AU - Ye L AD - Department of cardiothoracic surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Zhang, Min AU - Zhang M AD - Department of cardiothoracic surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Ren, Guosheng AU - Ren G AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Tao, Qian AU - Tao Q AD - Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. AD - Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK-Shenzhen Research Institute, Hong Kong. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200112 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (CXXC1 protein, human) RN - 0 (Repressor Proteins) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 0 (ZNF350 protein, human) RN - 0 (ZNF471 protein, human) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase 10) SB - IM MH - Animals MH - Apoptosis/genetics MH - Cell Line, Tumor/metabolism MH - DNA Methylation MH - Disease Models, Animal MH - Down-Regulation MH - Esophageal Neoplasms/pathology MH - Esophageal Squamous Cell Carcinoma/*genetics MH - Female MH - Gene Silencing MH - Genes, Tumor Suppressor/drug effects MH - Humans MH - Mice MH - Mice, Nude MH - Mitogen-Activated Protein Kinase 10/*metabolism MH - Promoter Regions, Genetic MH - Repressor Proteins/chemistry/*genetics MH - Signal Transduction/genetics MH - Trans-Activators/*chemistry/genetics MH - Transcription Factors/metabolism MH - Xenograft Model Antitumor Assays/methods PMC - PMC7019175 OTO - NOTNLM OT - CpG methylation OT - MAPK10/JNK3 OT - ZNF471 OT - esophageal OT - zinc finger protein COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2020/02/25 06:00 MHDA- 2021/04/15 06:00 PMCR- 2020/01/01 CRDT- 2020/02/25 06:00 PHST- 2019/04/18 00:00 [received] PHST- 2019/12/04 00:00 [accepted] PHST- 2020/02/25 06:00 [entrez] PHST- 2020/02/25 06:00 [pubmed] PHST- 2021/04/15 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - thnov10p2243 [pii] AID - 10.7150/thno.35861 [doi] PST - epublish SO - Theranostics. 2020 Jan 12;10(5):2243-2259. doi: 10.7150/thno.35861. eCollection 2020.