Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et Biophysica Acta-Gene Regulatory Mechanisms Pub Date : 2023-06-01 DOI:10.1016/j.bbagrm.2023.194941

Dongnan Ping , Xiaofan Pu , Guoping Ding , Chaolei Zhang , Junbin Jin , Chengjie Xu , Jiazheng Liu , Shengnan Jia , Liping Cao

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Abstract

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.

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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

胰腺导管腺癌是一种预后不良的高度恶性肿瘤。作为一种肿瘤抑制剂，Sirtuin4(SIRT4)在PDAC中的特异性抑瘤机制尚不明确。本研究发现SIRT4通过影响线粒体稳态抑制PDAC。SIRT4去乙酰化SEL1L的赖氨酸547，并增加E3泛素连接酶HRD1的蛋白水平。作为内质网相关蛋白降解(ERAD)的核心成员，HRD1-SEL1L复合体最近被报道调节线粒体，尽管其机制尚未完全描述。在这里，我们发现SEL1L-HRD1复合物的增加降低了线粒体蛋白ALKBH1的稳定性。ALKBH1的下调随后阻断了线粒体dna编码基因的转录，导致线粒体损伤。最后，我们发现了一种假定的SIRT4刺激剂Entinostat，它可以上调SIRT4的表达，并在体内和体外有效地抑制胰腺癌。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms 生物-生化与分子生物学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

44 days

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.