Dataset Information

ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma.

ABSTRACT: Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K-AKT-mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2-AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the antitumor efficacy of sunitinib in ccRCC.

Significance

ZDHHC2 confers sunitinib resistance to clear cell renal cell carcinoma by catalyzing AGK palmitoylation to activate the AKT-mTOR pathway.

SUBMITTER: Sun Y

PROVIDER: S-EPMC10267682 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma.

Sun Yan Y Zhu Liang L Liu Pian P Zhang Huan H Guo Feng F Jin Xin X

Cancer research 20230601 12

Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitini ...[more]

PMID: 37078777

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Project description:BackgroundThere is growing evidence that tripartite motif-containing protein 44 (TRIM44) plays crucial role in tumor development. However, the underlying mechanism of this deubiquitinating enzyme remains unclear.MethodsLarge clinical samples were used to detect TRIM44 expression and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of TRIM44 induced tumor progression. Co-immunoprecipitation (Co-IP) assays and mass spectrometric analyses were applied to verify the interacting proteins of TRIM44.ResultsWe found that TRIM44 was commonly amplified in melanoma tissues compared with paratumoral tissues. TRIM44 expression also positively correlated with more aggressive clinicopathological features, such as Breslow depth (p = 0.025), distant metastasis (p = 0.012), and TNM stage (p = 0.002). Importantly, we found that TRIM44 was an independent indicator of prognosis for melanoma patients. Functionally, overexpression of TRIM44 facilitated cell invasion, migration, apoptosis resistance and proliferation in vitro, and promoted lung metastasis and tumorigenic ability in vivo. Importantly, high level of TRIM44 induced melanoma cell epithelial-mesenchymal transition (EMT), which is one of the most important mechanisms for the promotion of tumor metastasis. Mechanistically, high levels of TRIM44 increased the levels of p-AKT (T308) and p-mTOR (S2448), and a specific AKT inhibitor inhibited TRIM44-induced tumor progression. Co-IP assays and mass spectrometric analyses indicated that TRIM44 overexpression induces cell EMT through activating AKT/mTOR pathway via directly binding and stabilizing TOLL-like receptor 4 (TLR4), and TLR4 interference impeded TRIM44 induced tumor progression. Moreover, we demonstrated that TRIM44 is the target of miR-26b-5p, which is significantly downregulated in melanoma tissues and may be responsible for the overexpression of TRIM44.ConclusionsTRIM44, regulated by miR-26b-5p, promotes melanoma progression by stabilizing TLR4, which then activates the AKT/mTOR pathway. TRIM44 shows promise as a prognostic predictor and a therapeutic target for melanoma patients.

Dataset Information

ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma.

Significance

Publications

ZDHHC2-Mediated AGK Palmitoylation Activates AKT-mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma.

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