Dataset Information

HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.

ABSTRACT: YTH domain family 2 (YTHDF2) is the first identified N6-methyladenosine (m⁶ A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90β) and STIP1 homology and U-box-containing protein 1 (STUB1) physically interact with YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of HSP90β is required for its interaction with STUB1 and YTHDF2. HSP90β inhibits the STUB1-induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90β and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90β is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90β. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC.

SUBMITTER: Liao Y

PROVIDER: S-EPMC10520652 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.

Liao Yuning Y Liu Yuan Y Yu Cuifu C Lei Qiucheng Q Cheng Ji J Kong Weiyao W Yu Yuanhui Y Zhuang Xuefen X Sun Wenshuang W Yin Shusha S Cai Gengxi G Huang Hongbiao H

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230728 27

YTH domain family 2 (YTHDF2) is the first identified N6-methyladenosine (m<sup>6</sup> A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90β) and STIP1 h ...[more]

PMID: 37515378

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Project description:BackgroundSorafenib is the first-line treatment for advanced-stage hepatocellular carcinoma (HCC). Several studies have shown that the up-regulation of β-catenin plays a role in sorafenib resistance in HCC; however, the mechanism associated with this phenomenon remains elusive.MethodsWestern blotting, flow cytometry, and an evaluation of IC50 values were used to confirm the role of β-catenin in HCC sorafenib resistance. Immunoprecipitation and western blotting were then performed to identify regulatory interactions between β-catenin and Nek2. Further, western blotting, flow cytometry, and an in vivo xenograft model were used to evaluate the function of Nek2 in HCC sorafenib resistance, whereas rescue experiments were performed to confirm that Nek2 induces sorafenib resistance via β-catenin. Finally, western blotting and immunohistochemistry were used to evaluate the expression level of Nek2 in paired HCC and non-tumor tissues.ResultsWe showed that β-catenin could suppress sorafenib-induced apoptosis and cell growth inhibition in HCC cell lines. By screening β-catenin-interacting proteins, we found that Nek2 could bind β-catenin in sorafenib-treated HCC cell lines. Our results also showed that Nek2 stabilizes β-catenin and promotes its translocation to the nucleus, consequently activating the transcription of downstream target genes. We further confirmed that Nek2 could induce sorafenib resistance in HCC cell lines, and that β-catenin was the key element involved in this process. Further, a xenograft tumor model showed that Nek2 knockdown could improve the anti-tumor effect of sorafenib, whereas an analysis of tumor proteins showed that Nek2 regulates β-catenin protein levels and its nuclear translocation in vivo. In addition, Nek2 was found to be up-regulated in HCC tissue, and especially in advanced-stage disease.ConclusionsOur study proves that Nek2 induces HCC sorafenib resistance via β-catenin and suggests a novel therapeutic strategy to improve the anti-tumor effects of sorafenib in HCC.

Project description:BackgroundVascular endothelial growth factor receptors (VEGFRs) are the major receptors involved in endothelial cell-dependent tumor angiogenesis. There are studies account for the effects of Hsp90 on angiogenesis, but the role and mechanism of Hsp90β isoforms and NVP-BEP800, a specific inhibitor of Hsp90β, in tumor angiogenesis is rarely mentioned.MethodsImmunohistochemistry and statistical analysis was used to evaluate the correlation between Hsp90β expression, CD31 endothelial cell-dependent vessel density, and VEGFRs expression in tissue samples of 96 HCCs. Kaplan-Meier survival analysis and COX proportional hazards analysis the relation of Hsp90β and prognosis. HUVEC cells were transfected with Hsp90β or treated with NVP-BEP800, and then cell proliferation, migration, invasion and tube formation were investigated. The VEGFR1 and VEGFR2 expression was determined by Western blot and immunofluorescence. The VEGFR1 and VEGFR2 promoter activities were detected by dual luciferase report system. In vivo, the angiogenesis promotion of Hsp90β and anti-angiogenesis efficacy of NVP-BEP800 was tested in HCC xenograft models. Histological analysis was performed on tumor samples to evaluate Hsp90β, VEGFRs expression and MVD.ResultsThis study investigated the correlation between Hsp90β expression and CD31+ endothelial cell-dependent vessel density. Hsp90β promoted VEGFRs expression by increasing their promoter activities. The proliferation, migration, invasion, and tube formation activities of human endothelial cells significantly increased when Hsp90β was overexpressed. NVP-BEP800 down-regulated VEGFRs expression to significantly reduce tubular differentiation, as well as endothelial cell proliferation, migration, and invasion. Furthermore, NVP-BEP800 decreased VEGFR1 and VEGFR2 promoter activities. In vivo, Hsp90β promoted VEGFRs and CD31 expression in human hepatocellular carcinoma tumor xenografts and was associated with increased tumor microvessel density. After 18 days of treatment with 30 mg/kg/day NVP-BEP800, VEGFRs and CD31 expression significantly decreased.ConclusionHsp90β induced endothelial cell-dependent tumor angiogenesis by activating VEGFRs transcription. NVP-BEP800 has potential as a therapeutic strategy for inhibiting tumor angiogenesis by decreasing endothelial cell progression and metastasis. It can help develop a therapeutic strategy for tumor treatment through the inhibition of endothelial cell progression and metastasis.

Dataset Information

HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.

Publications

HSP90β Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.

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