Hydroquinone destabilizes BIM mRNA through upregulation of p62 in chronic myeloid leukemia cells

Studies have shown that hydroquinone (HQ), a benzene metabolite, induces Autophagy and Apoptosis in leukemia cells. We found that HQ-induced Autophagy was cytotoxic to acute myeloid leukemia U937 cells but had a protective effect against Apoptosis in chronic myeloid leukemia (CML) K562 cells. HQ-induced Autophagy downregulated p62 expression in U937 cells, whereas it upregulated p62 expression in K562 cells regardless of autophagic flux. We also investigated the mechanism of p62 expression induction by HQ in K562 cells. Increased p62 expression in K562 cells reduced BIM mRNA stability and protein expression, which conferred resistance against the BH3 mimetics ABT-199 (BCL2 inhibitor) and A-1210477 (MCL1 inhibitor). K562/HQ cells, selected by the continuous exposure of K562 cells to HQ, also showed increased p62 expression and decreased Bim expression. HQ-induced SIRT3 expression promoted the upregulation of TET3 expression and JNK-mediated Sp1 phosphorylation, thereby increasing p62 expression in K562 and K562/HQ cells. Chromatin immunoprecipitation assay revealed that TET3-mediated DNA demethylation and JNK-mediated Sp1 phosphorylation promoted Sp1 recruitment to the p62 promoter. In CML KU812 cells, HQ induced p62 expression and downregulated Bim expression via a similar pathway. Collectively, our data indicate that HQ induces the upregulation of p62 expression in K562, KU812, and K562/HQ cells, increasing their resistance to BCL2 and MCL1 inhibition by reducing Bim expression. Thus, our findings propose a mechanism by which HQ induces the malignant progression of CML cells.