Cell death & disease · 2022
Stabilization of SAMHD1 by NONO is crucial for Ara-C resistance in AML.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zhang Feifei, Sun Jun, Tang Xiaofeng, Liang Yiping, Jiao Quanhui, Yu Bo, Dai Zhengzai, Yuan Xuhui, Li Jiayu, Yan Jinhua, Zhang Zhiping, Fan Song, Wang Min, Hu Haiyan, Zhang Changhua, Lv Xiao-Bin
Аннотация
Cytarabine (Ara-C) is the first-line drug for the treatment of acute myelogenous leukemia (AML). However, resistance eventually develops, decreasing the efficacy of Ara-C in AML patients. The expression of SAMHD1, a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, has been reported to be elevated in Ara-C-resistant AML patients and to play a crucial role in mediating Ara-C resistance in AML. However, the mechanism by which SAMHD1 is upregulated in resistant AML remains unknown. In this study, NONO interacted with and stabilized SAMHD1 by inhibiting DCAF1-mediated ubiquitination/degradation of SAMHD1. Overexpression of NONO increased SAMHD1 expression and reduced the sensitivity of AML cells to Ara-C, and downregulation of NONO had the opposite effects. In addition, the DNA-damaging agents DDP and adriamycin (ADM) reduced NONO/SAMHD1 expression and sensitized AML cells to Ara-C. More importantly, NONO was upregulated in Ara-C-resistant AML cells, resulting in increased SAMHD1 expression in resistant AML cells, and DDP and ADM treatment resensitized resistant AML cells to Ara-C. This study revealed the mechanism by which SAMHD1 is upregulated in Ara-C-resistant AML cells and provided novel therapeutic strategies for Ara-C-resistant AML.