Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine

• Published in: The Journal of biological chemistry Vol. 299; no. 1; p. 102798
• Main Authors: Shang, Qin, Pan, Chengyun, Zhang, Xi, Yang, Tonghua, Hu, Tianzhen, Zheng, Lin, Cao, Shuyun, Feng, Cheng, Hu, Xiuying, Chai, Xiao, Wang, Jishi, Fang, Qin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023; American Society for Biochemistry and Molecular Biology
• Subjects: 8-hydroxyguanine DNA glycosidase; acute myeloid leukemia; Apoptosis; Cell Nucleus - metabolism; cytarabine; Cytarabine - therapeutic use; DNA Glycosylases - metabolism; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; nuclear factor E2–related factor 2; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; resistance; cytarabine; si-OGG1; IHC; OGG1; BM; ChIP; DDR; acute myeloid leukemia; Nrf2; qPCR; IF; 8-OHdG; AML; CON; ICC; resistance; BER; 8-hydroxyguanine DNA glycosidase; Ara-C; CT; EV; FCM; p-AKT; NC; NOD/SCID; nuclear factor E2–related factor 2; si-Nrf2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2022.102798

Chemotherapy resistance is the dominant challenge in the treatment of acute myeloid leukemia (AML). Nuclear factor E2–related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Nevertheless, the potential molecular mechanism of Nrf2 regulating the base excision repair pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and base excision repair pathway gene encoding 8-hydroxyguanine DNA glycosidase (OGG1) was associated with AML disease progression. In vitro, Nrf2 and OGG1 were highly expressed in drug-resistant leukemia cells. Upregulation of Nrf2 in leukemia cells by lentivirus transfection could decrease the sensitivity of leukemia cells to cytarabine, whereas downregulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cells. Our chromatin immunoprecipitation assay revealed that Nrf2 could bind to the promoter of OGG1. Furthermore, the use of OGG1 inhibitor TH5487 could partially reverse the inhibitory effect of upregulated Nrf2 on leukemia cell apoptosis. In vivo, downregulation of Nrf2 could increase the sensitivity of leukemia cell to cytarabine and decrease OGG1 expression. Mechanistically, Nrf2–OGG1 axis–mediated AML resistance might be achieved by activating the AKT signaling pathway to regulate downstream apoptotic proteins. Thus, this study reveals a novel mechanism of Nrf2-promoting drug resistance in leukemia, which may provide a potential therapeutic target for the treatment of drug-resistant/refractory leukemia.