Abstract
Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying mechanisms driving this heterogeneity is essential for developing effective therapeutic strategies. This study revealed that ubiquitin B (UBB) is downregulated in ccRCC, which adversely affects the survival of ccRCC patients. UBB exerts regulatory control over vascular endothelial growth factor A (VEGFA) by directly interacting with specificity protein 1 (SP1), consequently exerting significant influence on angiogenic processes. Subsequently, we validated that DNA methyltransferase 3 alpha (DNMT3A) is located in the promoter of UBB to epigenetically inhibit UBB transcription. Additionally, we found that an unharmonious UBB/VEGFA ratio mediates pazopanib resistance in ccRCC. These findings underscore the critical involvement of UBB in antiangiogenic therapy and unveil a novel therapeutic strategy for ccRCC.
© 2024. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis
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Animals
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Carcinoma, Renal Cell* / blood supply
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Carcinoma, Renal Cell* / drug therapy
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Carcinoma, Renal Cell* / genetics
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Carcinoma, Renal Cell* / metabolism
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Carcinoma, Renal Cell* / pathology
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Cell Line, Tumor
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methyltransferase 3A / metabolism
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Down-Regulation*
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Drug Resistance, Neoplasm / genetics
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Indazoles / pharmacology
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Indazoles / therapeutic use
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Kidney Neoplasms* / blood supply
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Kidney Neoplasms* / drug therapy
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Kidney Neoplasms* / genetics
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Kidney Neoplasms* / metabolism
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Kidney Neoplasms* / pathology
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Male
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Mice
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Neovascularization, Pathologic* / genetics
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Neovascularization, Pathologic* / metabolism
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Neovascularization, Pathologic* / pathology
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Promoter Regions, Genetic
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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Sp1 Transcription Factor* / genetics
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Sp1 Transcription Factor* / metabolism
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Sulfonamides / pharmacology
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Ubiquitin / metabolism
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Vascular Endothelial Growth Factor A* / genetics
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Vascular Endothelial Growth Factor A* / metabolism
Substances
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Sp1 Transcription Factor
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Vascular Endothelial Growth Factor A
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VEGFA protein, human
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Pyrimidines
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SP1 protein, human
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Indazoles
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DNA Methyltransferase 3A
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pazopanib
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DNMT3A protein, human
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Sulfonamides
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Ubiquitin
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DNA (Cytosine-5-)-Methyltransferases