E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2.

IF 3.3 3区 医学 Q2 ONCOLOGY
Shuiping Liu, Lvjia Zhuo, Lu Chen, Ying He, Xudong Chen, Hao Zhang, Yuan Zhou, Ziheng Ni, Shujuan Zhao, Xiaotong Hu
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引用次数: 0

Abstract

We previously reported that RNF148 was involved in the ubiquitination-mediated degradation of CHAC2. However, its molecular mechanism was not determined. In this study, we investigated the role and mechanism of RNF148 in the progression of colorectal cancer (CRC), especially in the process of ubiquitination-mediated degradation of CHAC2. Our results revealed that RNF148 was upregulated in most CRC tissues, and its expression significantly correlated with the 3-year overall survival rate and most clinicopathological parameters of CRC patients. Furthermore, RNF148 served as an independent prognostic biomarker of CRC and promoted CRC cell proliferation and migration while inhibiting cell apoptosis and sensitivity to 5-FU. Mechanistically, RNF148 used its protease-associated domain to bind to the CHAC domain of CHAC2 and target it for degradation. In addition, we identified two phosphorylation and three ubiquitination residues of CHAC2 and identified Y118 and K102 as the critical phosphorylation and ubiquitination residues, respectively. We also identified CHAC2's and RNF148's interacting proteins and discovered their potential interaction network. In conclusion, our current study unveiled the role of RNF148 in CRC and the mechanism of RNF148 in the ubiquitination-mediated degradation of CHAC2, which shed light on providing potential prognostic biomarkers and molecular targets for CRC patients.

E3泛素连接酶RNF148通过泛素化介导的CHAC2降解在结直肠癌中发挥癌基因的功能。
我们曾报道 RNF148 参与了泛素化介导的 CHAC2 降解。然而,其分子机制尚未确定。在本研究中,我们研究了 RNF148 在结直肠癌(CRC)进展过程中的作用和机制,尤其是在泛素化介导的 CHAC2 降解过程中的作用和机制。结果发现,RNF148在大多数CRC组织中上调,其表达与CRC患者的三年总生存率和大多数临床病理参数显著相关。此外,RNF148还是CRC的一个独立预后生物标志物,它能促进CRC细胞的增殖和迁移,同时抑制细胞凋亡和对5-FU的敏感性。从机理上讲,RNF148利用其蛋白酶相关结构域与CHAC2的CHAC结构域结合,并靶向降解CHAC2。此外,我们还发现了 CHAC2 的两个磷酸化残基和三个泛素化残基,并确定 Y118 和 K102 分别为关键的磷酸化残基和泛素化残基。我们还鉴定了 CHAC2 和 RNF148 的互作蛋白,并发现了它们潜在的互作网络。总之,我们目前的研究揭示了RNF148在CRC中的作用以及RNF148在泛素化介导的CHAC2降解过程中的机制,为CRC患者提供了潜在的预后生物标志物和分子靶标。
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
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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