1. Academic Validation
  2. HDAC1-induced epigenetic silencing of ASPP2 promotes cell motility, tumour growth and drug resistance in renal cell carcinoma

HDAC1-induced epigenetic silencing of ASPP2 promotes cell motility, tumour growth and drug resistance in renal cell carcinoma

  • Cancer Lett. 2018 Sep 28;432:121-131. doi: 10.1016/j.canlet.2018.06.009.
Huayi Li 1 Xingwen Wang 1 Cheng Zhang 2 Yiwei Cheng 2 Miao Yu 3 Kunming Zhao 1 Wenjie Ge 1 Anyong Cai 1 Yao Zhang 1 Fengtong Han 1 Ying Hu 4
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China.
  • 2 Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150006, China.
  • 3 School of Chemistry, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China.
  • 4 School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen 518055, China. Electronic address: huying@hit.edu.cn.
Abstract

Renal cell carcinoma (RCC) is highly resistant to chemotherapies. The lack of efficacious treatment for metastatic RCC has led to a poor 5-year survival rate. Here, we found that Apoptosis-stimulating protein of p53-2(ASPP2) was frequently decreased in primary RCC tissues in comparison with non-tumoural kidney controls. Decreased ASPP2 was correlated with high grades and poor outcomes of RCC. Further studies revealed that ASPP2 downregulation promoted EMT and increased resistance to 5-Fluorouracil (5-FU)-induced Apoptosis. To this end, the regulatory mechanisms of ASPP2 were further explored. Our data revealed that ASPP2 was inhibited by histone deacetylatlase 1 (HDAC1), which acted by preventing the binding between transcription factor (E2F1) and the ASPP2 promoter. Of particular importance, HDAC1 Inhibitor vorinostat restored ASPP2 transcription and produced a synergistic effect with 5-FU in elevating ASPP2, promoting Apoptosis and inhibiting EMT in both in vitro and in vivo RCC models. In summary, our data not only highlight an important role of ASPP2 in RCC progression and drug resistance, but also reveal new regulatory mechanisms of ASPP2, which provides important insights into novel treatment strategies by targeting ASPP2 dysregulation in RCC.

Keywords

5-Fluorouracil and renal cell carcinoma; ASPP2; Apoptosis; Vorinostat.

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