Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway

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. KDM5A knockdown using 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 (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown 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 CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP 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 CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

 

Comments：

This study suggests that KDM5A is upregulated in liver cancer tissue and cell lines, and its knockdown using a gene interference strategy suppresses the growth of liver cancer in vitro and in vivo. Additionally, pharmacological inactivation of KDM5A with CPI-455 enhances the cytotoxicity of cisplatin (CDDP) in liver cells. The combined treatment of CPI-455 and CDDP induces apoptosis and mitochondrial dysfunction. The study also found that knockdown or inactivation of KDM5A leads to the downregulation of ROCK1, an oncogene that regulates the activation of the PTEN/AKT signaling pathway. Overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. Finally, in HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. This study suggests that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

Related Products

Cat.No.	Product Name	Information
S6389	CPI-455	CPI-455 is a specific KDM5 inhibitor with an IC50 of 10 nM for full-length KDM5A in enzymatic assays. CPI-455 shows over 200-fold selectivity for KDM5 relative to KDM2, 3, 4, 6, and 7 enzymes.

Related Targets

Histone Demethylase