Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY
Liyuan Qian, Zhentao Liang, Zihao Wang, Jiuru Wang, Xin Li, Jingmin Zhao, Zihai Li, Lizhao Chen, Yongai Liu, Ying Ju, Changfei Li, Songdong Meng
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引用次数: 0

Abstract

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlying mechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96 promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, and its stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular docking showed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. The binding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCC patients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered a novel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination. These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

细胞 gp96 通过阻断肝细胞癌中 NR5A2 SUMOylation 和泛素化来上调 AFP 的表达。
甲胎蛋白(AFP)是诊断肝细胞癌(HCC)最广泛使用的生物标志物。然而,相当一部分 HCC 患者血清中的甲胎蛋白水平正常或略有升高,其潜在机制尚未完全明了。在本研究中,我们提供了体外和体内证据,证明热休克蛋白 gp96 在转录水平上促进了 HCC 中 AFP 的表达。研究发现,NR5A2是AFP基因的关键转录因子,gp96增强了其稳定性。通过共免疫沉淀、GST pull-down和分子对接进行的进一步机理研究表明,gp96和SUMO E3连接酶RanBP2在跨越aa 507至aa 539的位点上竞争性地与NR5A2结合。gp96的结合抑制了NR5A2的SUMO化、泛素化和随后的降解。此外,对 HCC 患者的临床分析表明,肿瘤中 gp96 的表达与血清 AFP 水平呈正相关。因此,我们的研究发现了一种新的机制,即gp96通过直接影响客户蛋白的SUMO化和泛素化来调节其稳定性。这些发现将有助于设计更准确的基于 AFP 的 HCC 诊断和进展监测方法。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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