Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription. 2649 55

Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The molecular mechanism by which hepatocellular carcinoma (HCC) cells resist anoikis remains not fully understood. Here, we report that ZNF32 expression is markedly upregulated in HCC cells upon detachment. Enforced ZNF32 expression significantly promotes the anchorage-independent growth capability of HepG2 and Huh7 cells, whereas knockdown of ZNF32 results in increased apoptosis of HCC cells after detachment. Mechanistically, we demonstrate that ZNF32 overexpression suppresses the reactive oxygen species (ROS) accumulation and maintains mitochondrial membrane potential, leading to ATP, GSH and NADPH elevation and promoting HCC cell survival in response to suspension. Moreover, ZNF32 enhances the phosphorylation and activation of Src/FAK signaling. Src and FAK inhibitors effectively reverse ZNF32-induced anoikis resistance in HCC cells. Collectively, our findings not only reveal a novel and important mechanism by which ZNF32 contributes to anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling, but also suggest the potential therapeutic value of ZNF32 in HCC patients.
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PMID:ZNF32 induces anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling in hepatocellular carcinoma. 3043 40