Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Int J Mol Sci. 2020 Jul 17;21(14):5042. doi: 10.3390/ijms21145042.
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.
血管生成和血管内皮生长因子 (VEGF) 的表达在肾细胞癌 (RCC) 中增加。在伤口愈合过程中促进内皮细胞血管生成的转谷氨酰胺酶 2 (TGase 2) 在 RCC 中上调。肿瘤血管生成涉及三个领域：癌细胞、细胞外基质和内皮细胞。TGase 2 在细胞外基质中稳定 VEGF 并促进内皮细胞中 VEGFR-2 的核易位。然而，TGase 2 在癌细胞领域的血管生成中的作用尚不清楚。缺氧诱导因子 (HIF)-1α 介导的 VEGF 产生是癌细胞中血管生成诱导的基础。在这项研究中，我们表明 p53 在 RCC 中下调 HIF-1α，并且 p53 过表达会降低 VEGF 的产生。增加的 TGase 2 通过诱导 p53 降解来促进血管生成，从而激活 HIF-1α。HIF-1α 和 p53 与共因子 p300 的相互作用是稳定转录激活所必需的。我们发现 TGase 2 介导的 p53 耗竭增加了 p300 与 HIF-1α-p300 结合的可用性。临床前异种移植模型表明，TGase 2 抑制可逆转 RCC 中的血管生成。
