Downregulation of UBB potentiates SP1/VEGFA-dependent angiogenesis in clear cell renal cell carcinoma

Oncogene. 2024 May;43(18):1386-1396. doi: 10.1038/s41388-024-03003-6. Epub 2024 Mar 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis
  • Animals
  • Carcinoma, Renal Cell* / blood supply
  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / metabolism
  • Carcinoma, Renal Cell* / pathology
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methyltransferase 3A / metabolism
  • Down-Regulation*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • Kidney Neoplasms* / blood supply
  • Kidney Neoplasms* / drug therapy
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Male
  • Mice
  • Neovascularization, Pathologic* / genetics
  • Neovascularization, Pathologic* / metabolism
  • Neovascularization, Pathologic* / pathology
  • Promoter Regions, Genetic
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Sp1 Transcription Factor* / genetics
  • Sp1 Transcription Factor* / metabolism
  • Sulfonamides / pharmacology
  • Ubiquitin / metabolism
  • Vascular Endothelial Growth Factor A* / genetics
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • Sp1 Transcription Factor
  • Vascular Endothelial Growth Factor A
  • VEGFA protein, human
  • Pyrimidines
  • SP1 protein, human
  • Indazoles
  • DNA Methyltransferase 3A
  • pazopanib
  • DNMT3A protein, human
  • Sulfonamides
  • Ubiquitin
  • DNA (Cytosine-5-)-Methyltransferases