Inactivation of KDM5A Suppresses Growth and Enhances Chemosensitivity in Liver Cancer by Modulating ROCK1/PTEN/AKT Pathway

Abstract

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. Inhibition of KDM5A by a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin in liver cells. CPI-455 and cisplatin cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that inhibition or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and cisplatin cotreatment. In HCCLM3 xenografts, CPI-455 and cisplatin cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or cisplatin treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to cisplatin by modulating the ROCK1/PTEN/AKT signaling pathway.

Note:

Funding Information: This work was supported by Zhejiang Provincial Natural Science Foundation (LQ20H160055)， National Key Research and Development projects intergovernmental cooperation in science and technology of China (2018YFE0126900).

Declaration of Interests: The authors have no conflict of interest.

Ethics Approval Statement: All experiments using the human tissues were conducted under the approval of the Fifth Affiliated Hospital of Wenzhou Medical University. All patients gave informed consent. The animal experiments were approved by the Institutional Animal Care and Use Committee of the Fifth Affiliated Hospital of Wenzhou Medical University.

Keywords: KDM5A, CPI-455, Chemosensitivity, ROCK1, PTEN/AKT pathway；Liver cancer