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QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis.

ABSTRACT: Sunitinib is widely used as a first‑line treatment for advanced renal cell carcinoma (RCC). However, a number of patients with RCC who receive sunitinib develop drug resistance; and the biological mechanisms involved in resistance to sunitinib remain unclear. It has previously been suggested that the protein glutaminyl‑peptide cyclotransferase (QPCT) is closely related to sunitinib resistance in RCC. Thus, in the present study, in order to further examine the molecular mechanisms responsible for sunitinib resistance in RCC, sunitinib‑non‑responsive and ‑responsive RCC tissue and plasma samples were collected and additional experiments were performed in order to elucidate the molecular mechanisms responsible for sunitinib resistance in RCC. The upstream and downstream regulatory mechanisms of QPCT were also evaluated. On the whole, the data from the present study suggest that QPCT, CCCTC‑binding factor (CTCF) and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA) may be used as targets for predicting, reversing and treating sunitinib‑resistant RCC.

SUBMITTER: Zhao T

PROVIDER: S-EPMC8208629 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis.

Zhao Tangliang T Zhou Yulin Y Wang Qingyun Q Yi Xiaoming X Ge Silun S He Haowei H Xue Song S Du Bowen B Ge Jingping J Dong Jie J Qu Le L Wang Linhui L Zhou Wenquan W

International journal of oncology 20210526 1

Sunitinib is widely used as a first‑line treatment for advanced renal cell carcinoma (RCC). However, a number of patients with RCC who receive sunitinib develop drug resistance; and the biological mechanisms involved in resistance to sunitinib remain unclear. It has previously been suggested that the protein glutaminyl‑peptide cyclotransferase (QPCT) is closely related to sunitinib resistance in RCC. Thus, in the present study, in order to further examine the molecular mechanisms responsible for ...[more]

PMID: 34036385

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Project description:Rationale: Although sunitinib has been shown to improve the survival rate of advanced renal cell carcinoma (RCC) patients, poor drug response is a major challenge that reduces patient benefit. It is important to elucidate the underlying mechanism so that the therapeutic response to sunitinib can be restored. Methods: We used an Illumina HumanMethylation 850K microarray to find methylation-differentiated CpG sites between sunitinib-nonresponsive and -responsive RCC tissues and Sequenom MassARRAY methylation analysis to verify the methylation chip results. We verified glutaminyl peptide cyclotransferase (QPCT) expression in sunitinib-nonresponsive and -responsive RCC tissues via qRT-PCR, western blot and immunohistochemical assays. Then, cell counting kit 8 (CCK-8), plate colony formation and flow cytometric assays were used to verify the function of QPCT in RCC sunitinib resistance after QPCT intervention or overexpression. Chromatin immunoprecipitation (ChIP) was performed to clarify the upstream regulatory mechanism of QPCT. A human proteome microarray assay was used to identify downstream proteins that interact with QPCT, and co-immunoprecipitation (co-IP) and confocal laser microscopy were used to verify the protein chip results. Results: We found that the degree of methylation in the QPCT promoter region was significantly different between sunitinib-nonresponsive and -responsive RCC tissues. In the sunitinib-nonresponsive tissues, the degree of methylation in the QPCT promoter region was significantly reduced, and the expression of QPCT was upregulated, which correlated with a clinically poor response to sunitinib. A knockdown of QPCT conferred sunitinib sensitivity traits to RCC cells, whereas an overexpression of QPCT restored sunitinib resistance in RCC cells. Mechanistically, reducing the methylation degree of the QPCT promoter region by 5-aza-2'-deoxycytidine (decitabine) in RCC cells could increase the expression of QPCT and NF-κB (p65) bound to the QPCT promoter region, positively regulating its expression, while the hypermethylation in the QPCT promoter region could inhibit the binding of NF-κB (p65). QPCT could bind to HRAS and attenuate the ubiquitination of HRAS, thus increasing its stability and leading to the activation of the ERK pathway in RCC cells. Conclusion: QPCT may be a novel predictor of the response to sunitinib therapy in RCC patients and a potential therapeutic target.

Project description:Clear cell renal cell carcinoma (ccRCC) is tightly associated with VHL (von Hippel-Lindau tumor suppressor) mutation and dysregulated angiogenesis. Accumulating evidence indicates that antiangiogenic treatment abolishing tumor angiogenesis can achieve longer disease-free survival in patients with ccRCC. Atractylenolide I (ATL-I) is one of the main active compounds in Atractylodes macrocephala root extract and exhibits various pharmacological effects, including anti-inflammatory and antitumor effects. In this study, we revealed the potent antitumor activity of ATL-I in ccRCC. ATL-I exhibited robust antiangiogenic capacity by inhibiting EPAS1/HIF2α-mediated VEGFA production in VHL-deficient ccRCC, and it promoted autophagic degradation of EPAS1 by upregulating the ATPase subunit ATP6V0D2 (ATPase H+ transporting V0 subunit d2) to increase lysosomal function and facilitated fusion between autophagosomes and lysosomes. Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41 and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion. Moreover, ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy. Additionally, we found that ATL-I could decrease the level of EPAS1, which was upregulated in sunitinib-resistant cells, thus reversing sunitinib resistance. Collectively, our findings demonstrate that ATL-I is a robust antiangiogenic and antitumor lead compound with potential clinical application for ccRCC therapy.Abbreviations: ATL-I: atractylenolide I; ATP6V0D2: ATPase H+ transporting V0 subunit d2; CAM: chick chorioallantoic membrane; ccRCC: clear cell renal cell carcinoma; CTSB: cathepsin B; CTSD: cathepsin D; GO: Gene Ontology; HIF-1: HIF1A-ARNT heterodimer; HOPS: homotypic fusion and protein sorting; KDR/VEGFR: kinase insert domain receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; RCC: renal cell carcinoma; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TKI: tyrosine kinase inhibitor; V-ATPase: vacuolar-type H±translocating ATPase; VEGF: vascular endothelial growth factor; VHL: von Hippel-Lindau tumor suppressor.

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QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis.

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QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis.

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