Transglutaminase 2-mediated p53 depletion promotes angiogenesis by increasing hif-1α-p300 binding in renal cell carcinoma

Seon Hyeong Lee, Joon Hee Kang, Ji Sun Ha, Jae Seon Lee, Su Jin Oh, Hyun Jung Choi, Jaewhan Song, Soo Youl Kim

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10 Citations (Scopus)


Angiogenesis and the expression of vascular endothelial growth factor (VEGF) are increased in renal cell carcinoma (RCC). Transglutaminase 2 (TGase 2), which promotes angiogenesis in endothelial cells during wound healing, is upregulated in RCC. Tumor angiogenesis involves three domains: cancer cells, the extracellular matrix, and endothelial cells. TGase 2 stabilizes VEGF in the extracellular matrix and promotes VEGFR-2 nuclear translocation in endothelial cells. However, the role of TGase 2 in angiogenesis in the cancer cell domain remains unclear. Hypoxia-inducible factor (HIF)-1α-mediated VEGF production underlies the induction of angiogenesis in cancer cells. In this study, we show that p53 downregulated HIF-1α in RCC, and p53 overexpression decreased VEGF production. Increased TGase 2 promoted angiogenesis by inducing p53 degradation, leading to the activation of HIF-1α. The interaction of HIF-1α and p53 with the cofactor p300 is required for stable transcriptional activation. We found that TGase 2-mediated p53 depletion increased the availability of p300 for HIF-1α-p300 binding. A preclinical xenograft model suggested that TGase 2 inhibition can reverse angiogenesis in RCC.

Original languageEnglish
Article number5042
Pages (from-to)1-13
Number of pages13
JournalInternational journal of molecular sciences
Issue number14
Publication statusPublished - 2020 Jul 2

Bibliographical note

Funding Information:
Funding: This work was supported by a research grant from the National Cancer Center of Korea (# 1910060-2).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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