Weiyan Peng, Hongpeng Wang, Xuejuan Sun, Zhong Xu, Lingxiang Zhang, Lin Ye
{"title":"锌指蛋白82通过组蛋白去乙酰化酶调控p53蛋白稳定性,促进食管癌新辅助化疗。","authors":"Weiyan Peng, Hongpeng Wang, Xuejuan Sun, Zhong Xu, Lingxiang Zhang, Lin Ye","doi":"10.1038/s41419-025-07979-1","DOIUrl":null,"url":null,"abstract":"<p><p>Tumor suppressor genes silenced by CpG methylation uncover the molecular mechanism of tumorigenesis and potential tumor biomarkers. Our previous research found that the promoter of zinc-finger protein 82 (ZFP82) was highly methylated in multiple cancers, including esophageal cancer, which induces the occurrence and development of tumors. Here, we describe the frequent detection of methylation of the ZFP82 promoter CpG Island in patients who did not respond to neoadjuvant chemotherapy, indicating that ZFP82 may related to esophageal cancer chemo-resistance. We further verified that in esophageal cancer cells expressing wild-type p53, ZFP82 bound to the HDAC3 promoter and mediated its interaction with p53, leading to HDAC3 cleavage and reduction of p53 ubiquitin-dependent proteasomal degradation, thus enhancing wild-type p53 stability. In cells expressing mutant p53, ZFP82 interacted with HDAC3 to regulate the down-regulation of HSP 70, leading to degradation of mutant p53. Through both mechanisms, the restoration of ZFP82 enhanced the chemosensitivity in esophageal cancer cells expressing wild-type p53 or mutant p53, significantly inhibiting in vivo tumorigenicity of these cells. Analyses of the expression of ZFP82 and clinical data indicated that ZFP82 expression correlated with improved prognosis. Our results define a mechanism for p53 stabilization via ZFP82-dependent HDAC3 decay under genotoxic stress conditions and validate a candidate bio-marker of early prediction of patients who will respond to esophageal cancer neoadjuvant chemotherapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"694"},"PeriodicalIF":9.6000,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501244/pdf/","citationCount":"0","resultStr":"{\"title\":\"Zinc Finger Protein 82 regulates p53 protein stability through histone deacetylase and enhances neo-adjuvant chemotherapy in esophageal cancer.\",\"authors\":\"Weiyan Peng, Hongpeng Wang, Xuejuan Sun, Zhong Xu, Lingxiang Zhang, Lin Ye\",\"doi\":\"10.1038/s41419-025-07979-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Tumor suppressor genes silenced by CpG methylation uncover the molecular mechanism of tumorigenesis and potential tumor biomarkers. Our previous research found that the promoter of zinc-finger protein 82 (ZFP82) was highly methylated in multiple cancers, including esophageal cancer, which induces the occurrence and development of tumors. Here, we describe the frequent detection of methylation of the ZFP82 promoter CpG Island in patients who did not respond to neoadjuvant chemotherapy, indicating that ZFP82 may related to esophageal cancer chemo-resistance. We further verified that in esophageal cancer cells expressing wild-type p53, ZFP82 bound to the HDAC3 promoter and mediated its interaction with p53, leading to HDAC3 cleavage and reduction of p53 ubiquitin-dependent proteasomal degradation, thus enhancing wild-type p53 stability. In cells expressing mutant p53, ZFP82 interacted with HDAC3 to regulate the down-regulation of HSP 70, leading to degradation of mutant p53. Through both mechanisms, the restoration of ZFP82 enhanced the chemosensitivity in esophageal cancer cells expressing wild-type p53 or mutant p53, significantly inhibiting in vivo tumorigenicity of these cells. Analyses of the expression of ZFP82 and clinical data indicated that ZFP82 expression correlated with improved prognosis. Our results define a mechanism for p53 stabilization via ZFP82-dependent HDAC3 decay under genotoxic stress conditions and validate a candidate bio-marker of early prediction of patients who will respond to esophageal cancer neoadjuvant chemotherapy.</p>\",\"PeriodicalId\":9734,\"journal\":{\"name\":\"Cell Death & Disease\",\"volume\":\"16 1\",\"pages\":\"694\"},\"PeriodicalIF\":9.6000,\"publicationDate\":\"2025-10-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501244/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death & Disease\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41419-025-07979-1\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-025-07979-1","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Zinc Finger Protein 82 regulates p53 protein stability through histone deacetylase and enhances neo-adjuvant chemotherapy in esophageal cancer.
Tumor suppressor genes silenced by CpG methylation uncover the molecular mechanism of tumorigenesis and potential tumor biomarkers. Our previous research found that the promoter of zinc-finger protein 82 (ZFP82) was highly methylated in multiple cancers, including esophageal cancer, which induces the occurrence and development of tumors. Here, we describe the frequent detection of methylation of the ZFP82 promoter CpG Island in patients who did not respond to neoadjuvant chemotherapy, indicating that ZFP82 may related to esophageal cancer chemo-resistance. We further verified that in esophageal cancer cells expressing wild-type p53, ZFP82 bound to the HDAC3 promoter and mediated its interaction with p53, leading to HDAC3 cleavage and reduction of p53 ubiquitin-dependent proteasomal degradation, thus enhancing wild-type p53 stability. In cells expressing mutant p53, ZFP82 interacted with HDAC3 to regulate the down-regulation of HSP 70, leading to degradation of mutant p53. Through both mechanisms, the restoration of ZFP82 enhanced the chemosensitivity in esophageal cancer cells expressing wild-type p53 or mutant p53, significantly inhibiting in vivo tumorigenicity of these cells. Analyses of the expression of ZFP82 and clinical data indicated that ZFP82 expression correlated with improved prognosis. Our results define a mechanism for p53 stabilization via ZFP82-dependent HDAC3 decay under genotoxic stress conditions and validate a candidate bio-marker of early prediction of patients who will respond to esophageal cancer neoadjuvant chemotherapy.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism