Qian Zhang, Jin Man, Tianhe Zhao, Donglei Sun, Zunzhen Zhang
{"title":"YTHDF2通过降解人角质形成细胞中的PIDD1 mRNA促进砷诱导的恶性表型。","authors":"Qian Zhang, Jin Man, Tianhe Zhao, Donglei Sun, Zunzhen Zhang","doi":"10.1016/j.cbi.2024.111352","DOIUrl":null,"url":null,"abstract":"<p><p>Arsenic is a widespread environmental carcinogen, and its carcinogenic mechanism has been the focus of toxicology. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) binding protein YTH domain family protein 2 (YTHDF2) performs various biological functions by degrading m<sup>6</sup>A-modified mRNAs. However, the m<sup>6</sup>A-modified target mRNA of YTHDF2 in regulating arsenic carcinogenesis remains largely unknown. To explore the effect of YTHDF2 in regulating arsenic carcinogenicity, we exposed the human keratinocyte HaCaT cells to 1 μM sodium arsenite for 50 generations to create a cell model of arsenic carcinogenesis (HaCaT-T). Our results demonstrated that YTHDF2 protein levels were higher in HaCaT-T cells than HaCaT cells, and knockdown of YTHDF2 significantly inhibited arsenic-induced malignant phenotypes. In addition, m<sup>6</sup>A levels in HaCaT-T cells were remarkably elevated, accompanied by abnormal expression of m<sup>6</sup>A methyltransferases and m<sup>6</sup>A demethylases. Mechanistically, YTHDF2 bound to p53-induced death domain protein 1 (PIDD1) mRNA in an m<sup>6</sup>A-dependent manner, thereby promoting the degradation of PIDD1 mRNA. Moreover, the decay of PIDD1 mRNA inhibited the formation of PIDDosome complex that is essential for activating the apoptosis initiator caspase-2, leading to a decrease in caspase-2-dependent mitochondrial apoptosis and subsequently promoting the malignant phenotypes of HaCaT-T cells. Collectively, our study reveals the role of YTHDF2 in arsenic-induced malignant phenotypes of human keratinocytes through direct interaction with PIDD1 mRNA in an m<sup>6</sup>A-dependent manner, which provides new insight into the precise mechanism underlying arsenic-induced skin cancer.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111352"},"PeriodicalIF":0.0000,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"YTHDF2 promotes arsenic-induced malignant phenotypes by degrading PIDD1 mRNA in human keratinocytes.\",\"authors\":\"Qian Zhang, Jin Man, Tianhe Zhao, Donglei Sun, Zunzhen Zhang\",\"doi\":\"10.1016/j.cbi.2024.111352\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Arsenic is a widespread environmental carcinogen, and its carcinogenic mechanism has been the focus of toxicology. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) binding protein YTH domain family protein 2 (YTHDF2) performs various biological functions by degrading m<sup>6</sup>A-modified mRNAs. However, the m<sup>6</sup>A-modified target mRNA of YTHDF2 in regulating arsenic carcinogenesis remains largely unknown. To explore the effect of YTHDF2 in regulating arsenic carcinogenicity, we exposed the human keratinocyte HaCaT cells to 1 μM sodium arsenite for 50 generations to create a cell model of arsenic carcinogenesis (HaCaT-T). Our results demonstrated that YTHDF2 protein levels were higher in HaCaT-T cells than HaCaT cells, and knockdown of YTHDF2 significantly inhibited arsenic-induced malignant phenotypes. In addition, m<sup>6</sup>A levels in HaCaT-T cells were remarkably elevated, accompanied by abnormal expression of m<sup>6</sup>A methyltransferases and m<sup>6</sup>A demethylases. Mechanistically, YTHDF2 bound to p53-induced death domain protein 1 (PIDD1) mRNA in an m<sup>6</sup>A-dependent manner, thereby promoting the degradation of PIDD1 mRNA. Moreover, the decay of PIDD1 mRNA inhibited the formation of PIDDosome complex that is essential for activating the apoptosis initiator caspase-2, leading to a decrease in caspase-2-dependent mitochondrial apoptosis and subsequently promoting the malignant phenotypes of HaCaT-T cells. Collectively, our study reveals the role of YTHDF2 in arsenic-induced malignant phenotypes of human keratinocytes through direct interaction with PIDD1 mRNA in an m<sup>6</sup>A-dependent manner, which provides new insight into the precise mechanism underlying arsenic-induced skin cancer.</p>\",\"PeriodicalId\":93932,\"journal\":{\"name\":\"Chemico-biological interactions\",\"volume\":\" \",\"pages\":\"111352\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-12-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemico-biological interactions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cbi.2024.111352\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-biological interactions","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cbi.2024.111352","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
YTHDF2 promotes arsenic-induced malignant phenotypes by degrading PIDD1 mRNA in human keratinocytes.
Arsenic is a widespread environmental carcinogen, and its carcinogenic mechanism has been the focus of toxicology. N6-methyladenosine (m6A) binding protein YTH domain family protein 2 (YTHDF2) performs various biological functions by degrading m6A-modified mRNAs. However, the m6A-modified target mRNA of YTHDF2 in regulating arsenic carcinogenesis remains largely unknown. To explore the effect of YTHDF2 in regulating arsenic carcinogenicity, we exposed the human keratinocyte HaCaT cells to 1 μM sodium arsenite for 50 generations to create a cell model of arsenic carcinogenesis (HaCaT-T). Our results demonstrated that YTHDF2 protein levels were higher in HaCaT-T cells than HaCaT cells, and knockdown of YTHDF2 significantly inhibited arsenic-induced malignant phenotypes. In addition, m6A levels in HaCaT-T cells were remarkably elevated, accompanied by abnormal expression of m6A methyltransferases and m6A demethylases. Mechanistically, YTHDF2 bound to p53-induced death domain protein 1 (PIDD1) mRNA in an m6A-dependent manner, thereby promoting the degradation of PIDD1 mRNA. Moreover, the decay of PIDD1 mRNA inhibited the formation of PIDDosome complex that is essential for activating the apoptosis initiator caspase-2, leading to a decrease in caspase-2-dependent mitochondrial apoptosis and subsequently promoting the malignant phenotypes of HaCaT-T cells. Collectively, our study reveals the role of YTHDF2 in arsenic-induced malignant phenotypes of human keratinocytes through direct interaction with PIDD1 mRNA in an m6A-dependent manner, which provides new insight into the precise mechanism underlying arsenic-induced skin cancer.