Cellular gp96 upregulates AFP expression by blockade of NR5A2 SUMOylation and ubiquitination in HCC

Abstract

AFP is the most widely used biomarker for the diagnosis of hepatocellular carcinoma. 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 as well as 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 regulated by AFP and its stability was enhanced by gp96. A further mechanistic study by CO-IP, GST-pull down and molecular docking showed the competitive binding of gp96 and SUMO E3 ligase RanBP2 to NR5A2 at the sites spanning from aa 507 to 539. The binding of gp96 inhibited SUMOylating, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCC patients indicated that gp96 expression was positively correlated to serum AFP levels in tumors. Therefore, our study uncovered the novel regulatory mechanism of gp96 on 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.

NR5A2 gene affects the overall survival of LUAD patients by regulating the activity of CSCs through SNP pathway by OCLR algorithm and immune score

“…By comparing the structure of the NR5A gene in different organisms, it was found that the structure of the NR5A2 gene in various organisms is conserved, and there is obvious gene duplication in the evolutionary process, indicating that the NR5A2 gene is not prone to mutations and has high specificity in the expression of lung CSCs [ 56 ]. Furthermore, the variable shear location of the mutation site is associated with survival prognosis and the degree of drug resistance in patients with LUAD, which will be conducive to the drug guidance of second-line therapy and locating drug-resistant mutation gene sites, and will greatly improve the survival time of patients [ [57] , [58] , [59] , [60] , [61] ].…”

NR5A2 promotes the growth and metastasis of cutaneous squamous cell carcinoma A431 cells via the Wnt/β-catenin signaling pathway

“…8 In the research of hepatocellular carcinoma has shown that reducing NR5A2 expression using gene silencing technology can inhibit the process of its proliferation. 9 Additionally, NR5A2 was found to be highly expressed in Adriamycin-resistant breast cancer cells, and silencing NR5A2 expression reversed this cellular resistance. 10,11 NR5A2 has also been shown to be crucial for cell invasion and migration.…”

NR5A2 promotes malignancy progression and mediates the effect of cisplatin in cutaneous squamous cell carcinoma

“…8 A study on hepatocellular carcinoma showed that the downregulation of NR5A2 expression using gene silencing technology inhibits the process of cell proliferation. 9 Additionally, NR5A2 is also highly expressed in adriamycin-resistant breast cancer cells, and the silencing of NR5A2 expression leads to the reversal of cellular resistance. 10,11 Moreover, NR5A2 has also been shown to be crucial for cell invasion and migration.…”