Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex.
Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex.
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DOI：
10.1016/j.bbagrm.2023.194941
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发表时间：
2023-05
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影响因子：
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通讯作者：
Dongnan Ping;Xiaofan Pu;Guo-ping Ding;Chaolei Zhang;Junbin Jin;Chengjie Xu;Jiazheng Liu;Shengnan Jia;Liping Cao
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文献类型：
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作者：
Dongnan Ping;Xiaofan Pu;Guo-ping Ding;Chaolei Zhang;Junbin Jin;Chengjie Xu;Jiazheng Liu;Shengnan Jia;Liping Cao
胰腺导管腺癌是一种高度恶性的肿瘤，预后差。SIRT 4作为一种肿瘤抑制剂，其在PDAC中的特异性抑癌机制尚不清楚。在这项研究中，发现SIRT 4通过影响线粒体稳态来抑制PDAC。SIRT 4使SEL 1 L的赖氨酸547脱乙酰化，并增加E3泛素连接酶HRD 1的蛋白水平。HRD 1-SEL 1 L复合物作为内质网相关蛋白降解（ERAD）的核心成员，近年来被报道参与线粒体的调控，但其机制尚未完全阐明。在这里，我们发现SEL 1 L-HRD 1复合物的增加降低了线粒体蛋白ALKBH 1的稳定性。ALKBH 1的下调随后阻断线粒体DNA编码基因的转录，并导致线粒体损伤。最后，确定了一种假定的SIRT 4刺激剂，Entinostat，其上调SIRT 4的表达，并在体内和体外有效地抑制胰腺癌。
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 cancerin vivoandin vitro.