Dongnan Ping , Xiaofan Pu , Guoping Ding , Chaolei Zhang , Junbin Jin , Chengjie Xu , Jiazheng Liu , Shengnan Jia , Liping Cao
{"title":"Sirtuin4通过HRD1-SEL1L复合物的去乙酰化降低AlkB同源物1的稳定性，从而影响胰腺癌细胞的线粒体稳态","authors":"Dongnan Ping , Xiaofan Pu , Guoping Ding , Chaolei Zhang , Junbin Jin , Chengjie Xu , Jiazheng Liu , Shengnan Jia , Liping Cao","doi":"10.1016/j.bbagrm.2023.194941","DOIUrl":null,"url":null,"abstract":"<div><p><span><span><span>Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. As a tumor inhibitor, the specific tumor suppressor mechanism of Sirtuin4(SIRT4) in PDAC remains elusive. In this study, SIRT4 was found to inhibit PDAC by impacting mitochondrial </span>homeostasis. SIRT4 deacetylated lysine 547 of SEL1L and increased the protein level of an E3 </span>ubiquitin ligase<span> HRD1. As a central member of ER-associated protein degradation (ERAD), HRD1-SEL1L complex is recently reported to regulate the mitochondria, though the mechanism is not fully delineated. Here, we found the increase in SEL1L-HRD1 complex decreased the stability of a mitochondrial protein, ALKBH1. Downregulation of ALKBH1 subsequently blocked the transcription of mitochondrial DNA-coded genes, and resulted in mitochondrial damage. Lastly, a putative SIRT4 stimulator, Entinostat, was identified, which upregulated the expression of SIRT4 and effectively inhibited pancreatic cancer </span></span><em>in vivo</em> and <em>in vitro</em>.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 2","pages":"Article 194941"},"PeriodicalIF":2.6000,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex\",\"authors\":\"Dongnan Ping , Xiaofan Pu , Guoping Ding , Chaolei Zhang , Junbin Jin , Chengjie Xu , Jiazheng Liu , Shengnan Jia , Liping Cao\",\"doi\":\"10.1016/j.bbagrm.2023.194941\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span><span>Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. As a tumor inhibitor, the specific tumor suppressor mechanism of Sirtuin4(SIRT4) in PDAC remains elusive. In this study, SIRT4 was found to inhibit PDAC by impacting mitochondrial </span>homeostasis. SIRT4 deacetylated lysine 547 of SEL1L and increased the protein level of an E3 </span>ubiquitin ligase<span> HRD1. As a central member of ER-associated protein degradation (ERAD), HRD1-SEL1L complex is recently reported to regulate the mitochondria, though the mechanism is not fully delineated. Here, we found the increase in SEL1L-HRD1 complex decreased the stability of a mitochondrial protein, ALKBH1. Downregulation of ALKBH1 subsequently blocked the transcription of mitochondrial DNA-coded genes, and resulted in mitochondrial damage. Lastly, a putative SIRT4 stimulator, Entinostat, was identified, which upregulated the expression of SIRT4 and effectively inhibited pancreatic cancer </span></span><em>in vivo</em> and <em>in vitro</em>.</p></div>\",\"PeriodicalId\":55382,\"journal\":{\"name\":\"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms\",\"volume\":\"1866 2\",\"pages\":\"Article 194941\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2023-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1874939923000366\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1874939923000366","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. As a tumor inhibitor, the specific tumor suppressor mechanism of Sirtuin4(SIRT4) in PDAC remains elusive. In this study, SIRT4 was found to inhibit PDAC by impacting mitochondrial homeostasis. SIRT4 deacetylated lysine 547 of SEL1L and increased the protein level of an E3 ubiquitin ligase HRD1. As a central member of ER-associated protein degradation (ERAD), HRD1-SEL1L complex is recently reported to regulate the mitochondria, though the mechanism is not fully delineated. Here, we found the increase in SEL1L-HRD1 complex decreased the stability of a mitochondrial protein, ALKBH1. Downregulation of ALKBH1 subsequently blocked the transcription of mitochondrial DNA-coded genes, and resulted in mitochondrial damage. Lastly, a putative SIRT4 stimulator, Entinostat, was identified, which upregulated the expression of SIRT4 and effectively inhibited pancreatic cancer in vivo and in vitro.
期刊介绍：
BBA Gene Regulatory Mechanisms includes reports that describe novel insights into mechanisms of transcriptional, post-transcriptional and translational gene regulation. Special emphasis is placed on papers that identify epigenetic mechanisms of gene regulation, including chromatin, modification, and remodeling. This section also encompasses mechanistic studies of regulatory proteins and protein complexes; regulatory or mechanistic aspects of RNA processing; regulation of expression by small RNAs; genomic analysis of gene expression patterns; and modeling of gene regulatory pathways. Papers describing gene promoters, enhancers, silencers or other regulatory DNA regions must incorporate significant functions studies.
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