1. Academic Validation
  2. CDK9 inhibitors reactivate p53 by downregulating iASPP

CDK9 inhibitors reactivate p53 by downregulating iASPP

  • Cell Signal. 2020 Mar;67:109508. doi: 10.1016/j.cellsig.2019.109508.
Jiale Wu 1 Ying Liang 1 Yun Tan 1 Yigang Tang 1 Huaxin Song 1 Zhengyuan Wang 1 Yuntong Li 1 Min Lu 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Genomics, Shanghai Institute of Haematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 2 State Key Laboratory of Medical Genomics, Shanghai Institute of Haematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address: min.lu@shsmu.edu.cn.
Abstract

Loss of p53's tumor-suppressive function, either via TP53 mutation or hyperactive p53 inhibitory proteins, is one of the most frequent events in the development of human Cancer. Here, we describe a strategy of pharmacologically inhibiting iASPP, a negative regulator of p53, to restore wild-type p53's tumor-suppressive function. iASPP knockdown in the colon Cancer cell line HCT116 efficiently promoted p53's transcriptional activity and induced p53-dependent cell death, suggesting a key role for iASPP in silencing p53 in this cell line. Screening of a preclinical and clinical drug library using isogenic HCT116 cell models revealed that cyclin-dependent kinase 9 (CDK9) inhibitors preferentially inhibit p53+/+, rather than p53-/-, cells. Mechanistically, CDK9 inhibitors downregulated iASPP at the transcriptional level. This downregulation was dose- and time-dependent. CDK9 inhibitors further showed synergistic effects in killing p53+/+ HCT116 cells when combined with the MDM2 Inhibitor Nutlin-3. In a large TCGA pan-cancer cohort, iASPP overexpression predicted poor overall survival (OS) in wild-type p53 patients, with worse OS observed when MDM2 was simultaneously overexpressed. Our study identifies CDK9 inhibitors as p53-reactivating agents, and proposes a strategy to treat Cancer by efficiently reactivating p53 via the concurrent inhibition of iASPP and MDM2.

Keywords

CDK9 inhibitor; Concurrent inhibition; MDM2; iASPP; p53 reactivation.

Figures
Products