ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription

Abstract

Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro-oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment.

ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma

“…Our previous study identified two Sp1-response elements at the ZNF32 promoter regions −1318/−1304 and −43/−27. 35 An electrophoretic mobility shift assay (EMSA) confirmed that nuclear protein extracts from A549 cells might interact with probes containing the ZNF32 promoter-derived Sp1 binding sequences, and CIS treatment could further result in enhanced shifting (Figure 1f). In addition, Sp1 overexpression increased the formation of DNA-nucleoprotein complexes (Figure 1f).…”

“…Our previous study demonstrated that Sp1 could precisely regulate the transcription of ZNF32 in response to oxidative stress. 35 Furthermore, the transcription factor Sp1 has been shown to induce the transcription of drug resistance-associated genes. 36, 37 Thus, we examined whether ZNF32 expression could be regulated by Sp1 in response to drug induction.…”

“…34, 35 On the basis of these findings, we aimed to investigate whether ZNF32 could make cancer cells immune to cytotoxic drugs. In addition, our results indicate that ZNF32 is highly expressed in lung AC tissues; thus, we hypothesized that ZNF32 is associated with carcinogenesis and lung AC progression.…”

“…34 ZNF32 overexpression has been shown to markedly increase the ability of cells to protect against oxidative stress-induced injury. 35 These findings suggest that ZNF32 might enable the tolerance of cancer to anti-tumor drugs. Thus, the aim of the present study was to determine the role of ZNF32 in MDR in lung AC and to further identify the underlying mechanisms.…”

Levels of interleukin-6, superoxide dismutase and malondialdehyde in the lung tissue of a rat model of hypoxia-induced acute pulmonary edema

“…SOD is capable of resisting and blocking the damaging effects of oxygen free radicals on cells and initiating the timely repair of damage to cells caused by free radicals (17). Oxidative stress results from the excessive production of free radicals in the body, which can affect protein expression and other regulatory and response mechanisms (18). When induced by free radical and compensated stress, the antioxidant capacity of a cell or organism can increase, during which the phenomenon of transiently increased levels of SOD may be observed (19).…”