Epigenetic silencing of ASPP1 confers 5-FU resistance in clear cell renal cell carcinoma by preventing p53 activation

Inactivation of p53 has been shown to correlate with drug resistance in tumors. However, in clear cell renal cell carcinoma (ccRCC), p53 is rarely mutated, yet the tumors remain highly insensitive to the conventional chemotherapeutic drugs. The underlying mechanisms responsible for the non-genetic p53 inactivation remain obscure. Here, we report, for the first time, that Apoptosis Stimulating of P53 Protein 1 (ASPP1) was remarkably downregulated at both mRNA (about 3.9-fold) and protein (about 4.9-fold) levels in ccRCC human specimens in comparison with the paired normal controls. In addition, lower ASPP1 was closely related to the higher grade of tumors and shorter life expectancy of ccRCC patients, both with p < 0.001. We also find that CpG island hypermethylation at promoter region contributed to the suppression of ASPP1 expression in ccRCC that contained relatively low levels of ASPP1. Further functional studies demonstrated that forced expression ASPP1 not only significantly inhibited the growth rate of ccRCC, but also promoted sensitivity of ccRCC to the conventional chemotherapeutic drug 5-fluorouracil (5-FU)-induced apoptosis. Moreover, ASPP1 expression was accompanied with the apoptosis-prone alterations of p53 targets expression and p53 target PIG3 luciferase reporter activation. In contrast, ASPP1 knockdown promoted cell growth and prevent 5-FU-induced p53 activation and apoptosis. In conclusion, our results suggest that ASPP1 silencing is one of dominate mechanisms in inhibiting wild type p53 in ccRCC. ASPP1, therefore, may be potentially used as a promising biomarker for prognosis and therapeutic intervention in ccRCC.

International journal of cancer. 2017 Jul 10 [Epub]

Xingwen Wang, Yiwei Cheng, YiFu Zhu, Huayi Li, Wenjie Ge, Xiaoliang Wu, Kunming Zhao, Jinyang Yuan, Zhenglin Li, Shijian Jiang, Zhengbin Han, Qinghua Jiang, Qiong Wu, Tao Liu, Cheng Zhang, Miao Yu, Ying Hu

School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China., The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, China., School of Chemical Engineering and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, 150001, China., Shenzhen Luohu People's Hospital, Shenzhen Zhongxun Precision Medicine Research Institute, Shenzhen, Guangdong, 518001, China.