VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2.
VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2.
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VHL 缺陷通过下调 ALDH2 增强透明细胞肾细胞癌的蒽环类药物敏感性
DOI：
10.1038/ncomms15337
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发表时间：
2017-06-15
影响因子：
16.6
通讯作者：
Wang LS
中科院分区：
文献类型：
--
作者：
Gao YH;Wu ZX;Xie LQ;Li CX;Mao YQ;Duan YT;Han B;Han SF;Yu Y;Lu HJ;Yang PY;Xu TR;Xia JL;Chen GQ;Wang LS
约 70% 的透明细胞肾细胞癌 (ccRCC) 存在 von Hippel-Lindau (VHL) 缺陷，这导致了 ccRCC 的癌变和耐药性。在这里，我们表明，VHL 缺陷的 ccRCC 细胞以不依赖缺氧诱导因子的方式呈现增强的蒽环类药物细胞毒性。通过消减蛋白质组分析结合 RNAi 或过表达验证，发现乙醛脱氢酶 2 (ALDH2) 受 VHL 转录调节，有助于增强 ccRCC 细胞中的蒽环类药物细胞毒性。此外，VHL通过直接结合-130 bp至-160 bp的启动子来激活肝细胞核因子4α（HNF-4α）的转录来调节ALDH2表达。此外，ccRCC 样本中 VHL、HNF-4α 和 ALDH2 的蛋白表达呈正相关。这些发现将加深我们对 VHL 功能的理解，并为 ccRCC 患者的精准治疗提供线索。大约 70% 的透明细胞肾细胞癌 (ccRCC) 中 VHL 肿瘤抑制基因丢失。在这项研究中，作者证明这些肿瘤中 VHL 的丢失通过下调 ALDH2 增强了蒽环类化疗。
The von Hippel-Lindau (VHL) is deficient in ∼70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of −130 bp to −160 bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4α). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4α and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients. The VHL tumour suppressor gene is lost in approximately 70% of clear cell renal cell carcinoma (ccRCC). In this study, the authors demonstrate that VHL loss in these tumours augments anthracyclines chemotherapy by down-regulation of ALDH2.