IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yaqi Mo, Yamei Han, Yang Chen, Chunling Fu, Qing Li, Zhuang Liu, Mingming Xiao, Bo Xu
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引用次数: 0

摘要

蛋白质棕榈酰化是一种可逆的脂肪酰基修饰,在多种生理过程中发挥着重要功能。棕榈酰化失调常常与癌症的形成有关。S-棕榈酰化棕榈酰转移酶如何参与肝细胞癌(HCC)的发生和发展,目前尚不清楚。研究人员利用锌指DHHC型棕榈酰基转移酶20(ZDHHC20)基因敲除小鼠建立了化学致癌物二乙基亚硝胺(DEN)诱导的HCC模型和DEN联合CCl4诱导的HCC模型,以研究ZDHHC20在HCC肿瘤发生中的作用。通过棕榈酰化液相色谱-质谱分析、酰基生物素交换测定、共免疫沉淀、泛素化测定、蛋白半衰期测定和免疫荧光显微镜检查,探讨了ZDHHC20在HCC中的下游调控因子和相应机制。在两种HCC小鼠模型中,敲除ZDHHC20能显著减少化学药物诱导的体内肝癌发生。研究发现,97 个含有 123 个半胱氨酸位点的蛋白质以 ZDHHC20 依赖性的方式被棕榈酰化。其中,脂肪酸合成酶(FASN)的半胱氨酸 1471 和 1881 被 ZDHHC20 棕榈酰化。基因敲除或药物抑制 ZDHHC20 以及 FASN 关键半胱氨酸位点的突变(C1471S/C1881S)都会加速 FASN 的降解。此外,ZDHHC20介导的FASN棕榈酰化还通过E3泛素连接酶复合物SNX8-TRIM28与泛素-蛋白酶体途径竞争。我们的研究结果证明了ZDHHC20在促进肝癌发生中的关键作用,以及蛋白质棕榈酰化和泛素化修饰相互制约模式的内在机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis
Protein palmitoylation is a reversible fatty acyl modification that undertakes important functions in multiple physiological processes. Dysregulated palmitoylations are frequently associated with the formation of cancer. How palmitoyltransferases for S-palmitoylation are involved in the occurrence and development of hepatocellular carcinoma (HCC) is largely unknown. Chemical carcinogen diethylnitrosamine (DEN)-induced and DEN combined CCl4 HCC models were used in the zinc finger DHHC-type palmitoyltransferase 20 (ZDHHC20) knockout mice to investigate the role of ZDHHC20 in HCC tumourigenesis. Palmitoylation liquid chromatography-mass spectrometry analysis, acyl-biotin exchange assay, co-immunoprecipitation, ubiquitination assays, protein half-life assays and immunofluorescence microscopy were conducted to explore the downstream regulators and corresponding mechanisms of ZDHHC20 in HCC. Knocking out of ZDHHC20 significantly reduced hepatocarcinogenesis induced by chemical agents in the two HCC mouse models in vivo. 97 proteins with 123 cysteine sites were found to be palmitoylated in a ZDHHC20-dependent manner. Among these, fatty acid synthase (FASN) was palmitoylated at cysteines 1471 and 1881 by ZDHHC20. The genetic knockout or pharmacological inhibition of ZDHHC20, as well as the mutation of the critical cysteine sites of FASN (C1471S/C1881S) accelerated the degradation of FASN. Furthermore, ZDHHC20-mediated FASN palmitoylation competed against the ubiquitin-proteasome pathway via the E3 ubiquitin ligase complex SNX8-TRIM28. Our findings demonstrate the critical role of ZDHHC20 in promoting hepatocarcinogenesis, and a mechanism underlying a mutual restricting mode for protein palmitoylation and ubiquitination modifications.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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