NKD1 targeting PCM1 regulates the therapeutic sensitivity of HHT on colorectal cancer cells

Abstract Colorectal cancer (CRC) is the most common primary malignant tumor with a significantly higher incidence in the worldwide. Homoharringtonine (HHT) often used to treatment of acute leukemia. Recent research revealed it could be used for solid cancer therapy. However, the regulatory target and mechanism of HHT in CRC progression remain elusive. This study proved that HHT suppressed cell proliferation and promoted cell cycle arrest and apoptosis. Transcriptome sequence indicated that NKD1 was the target of HHT in CRC. HHT could suppress NKD1 expression in a concentration and time dependent manner. NKD1 was overexpressed in CRC tissues and depletion of NKD1 enhanced the therapeutic effect of HHT on CRC in vitro and vivo. Furthermore, proteomic analysis revealed that PCM1 involved in the process of cell proliferation and cell cycle regulated by NKD1. NKD1 interacts with PCM1, and NKD1 promotes the ubiquitination degradation of PCM1. Moreover, overexpression of PCM1 can effectively reverse the promoting effect of NKD1 interference on cell cycle arrest and apoptosis. These results suggested that the NKD1/PCM1 axis participated in mediating the therapeutic sensitivity of HHT to CRC. Our findings provide evidence for clinical application of NKD1-targeted therapy in improving HHT sensitivity for CRC treatment.