Abstract

Cisplatin is the effective chemotherapeutic drug in colon cancer treatment, but its therapeutic efficacy is limited by intrinsic or acquired drug resistance and detrimental side effects. Therefore, improving the effect of cisplatin chemotherapy remains a great challenge. The previous study identified that USP39 was relevant to cisplatin resistance of lung cancer. However, the function and mechanisms of USP39 regulating the chemosensitivity of cisplatin in colorectal cancer remain unclear. In this study, we reveal that USP39 is associated with colon cancer cells sensitivity to cisplatin. Depletion of USP39 enhances the cisplatin-induced apoptosis in HCT116 cells. Conversely, overexpression of USP39 attenuates apoptosis in RKO cells. Furthermore, we demonstrate that USP39 depletion promotes apoptosis induced by cisplatin, which is related with the induction of oxidative stress and DNA damage response. Further studies show that USP39 regulates cisplatin-induced apoptosis dependent on p53. The underlying mechanism is demonstrated by knocking down USP39, that results in p53 upregulation, associated with its prolonged half-life. Collectively, our findings reveal that USP39 might be a negative factor of the p53 mediated cisplatin sensitivity of colon cancer, and suggest USP39 as a potential molecular target for cisplatin chemotherapy of colon cancer. Graphical abstract