Stabilization of SAMHD1 by NONO is crucial for Ara-C resistance in AML.

Abstract

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.

• Authors: Feifei Zhang, Jun Sun, Xiaofeng Tang, Yiping Liang, Quanhui Jiao, Bo Yu, Zhengzai Dai, Xuhui Yuan, Jiayu Li, Jinhua Yan, Zhiping Zhang, Song Fan, Min Wang, Haiyan Hu, Changhua Zhang, Xiao-Bin Lv
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 7 Pg. 590 (07 08 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35803902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• DNA-Binding Proteins
• NONO protein, human
• RNA-Binding Proteins
• Cytarabine
• SAM Domain and HD Domain-Containing Protein 1
• SAMHD1 protein, human

Topics

• Cytarabine (pharmacology, therapeutic use)
• DNA-Binding Proteins (metabolism)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism)
• RNA-Binding Proteins
• SAM Domain and HD Domain-Containing Protein 1 (genetics, metabolism)