The Role Of ZNF304 In Metabolic Reprogramming And Chemotherapy Resistance In Lung Cancer

Background and purpose: The morbidity and mortality of lung cancer have been increasing in recent years,and it is one of the most common malignant tumors that threaten human health.Although chemotherapy has been routinely used in the treatment of lung cancer patients,the prognosis remains grim and drug resistance has been reported.Therefore,it is crucial to find new therapeutic targets for patients with lung adenocarcinoma.Zinc finger protein 304(ZNF304)plays a key role in transcriptional silencing of genes,regulation of cell survival,proliferation,apoptosis and differentiation during development.However,the role of the transcription factor ZNF304 in non-small cell lung cancer(NSCLC)and its clinical significance remain unclear.Methods: UALCAN(http://ualcan.path.uab.edu/analysis.html)was used to analyze the expression of ZNF304 in lung cancer,and https://kmplot.com/analysis/ was used to analyze the relationship between ZNF304 expression and clinical prognosis.Constructed NSCLC cell lines overexpressing and underexpressing ZNF304,and verified the protein expression of ZNF304 in the constructed cell lines by western blot method;the effect on proliferation ability and cloning ability was examined by MTT assay and soft agar cloning assay;The effect of growth was tested with a nude mouse model of subcutaneous xenografts.A549 cisplatin-resistant cell line was cultured using a concentration gradient method.The effect of ZNF304 on the expression of glycolysis and glutamine metabolism-related factors in NSCLC cells was detected by western blotting;the metabolites were detected by glucose detection kit,lactate detection kit,glutamine detection kit,and glutamate detection kit.The interaction between Myc and ZNF304 was detected by CO-IP.Results: The expression of ZNF304 was down-regulated in lung cancer tissues.Lower levels of ZNF304 were associated with poor survival.Downregulation of ZNF304 promoted H322M cell growth in vitro,whereas overexpression of ZNF304 inhibited A549 growth.Our results suggest that ZNF304 expression inhibits cellular glycolysis and glutamine metabolism.ZNF304 was down-regulated in A549 cisplatin-resistant cells,and overexpression enhanced the sensitivity of cells to cisplatin.In addition,ZNF304 interacts with C-Myc,suggesting that ZNF304 may inhibit the transcription of factors related to glycolysis and glutamine metabolism through interaction with C-Myc.Conclusion: ZNF304 acts as a tumor suppressor in lung cancer and is down-regulated,which can inhibit the metabolic reprogramming of NSCLC cells and enhance chemosensitivity.This study suggests that ZNF304 may be a potential target for non-small cell lung cancer therapy and addressing drug resistance.