ZNF148/PFKP/PD-L1 axis promotes non-small cell lung cancer proliferation, migration and glycolysis

Abstract

Aim: Cancer-related deaths are primarily caused by lung cancer around the world. The prognosis and burden of lung cancer must be improved by identifying novel biomarkers for diagnosis and treatment. In non-small cell lung cancer (NSCLC), the platelet isoform of phosphofructokinase 1 (PFKP) has been identified as a tumor-promoting oncogene. The current study examined the specific role that PFKP plays in NSCLC tumorigenesis, as well as the underlying mechanism.

Methods: A lung cancer dataset was obtained from the TCGA in order to examine the expression of PFKP. Using the Kaplan-Meier Plotter website, we calculated the overall survival (OS) along with the recurrence-free survivals (RFS) curves with high and low levels of PFKP in lung cancer. The mechanism by which zinc finger protein 148 (ZNF148) regulated PFKP/PD-L1 levels in NSCLC was investigated through chromatin immunoprecipitation (ChIP), qRT-PCR, and western blotting. In order to uncover ZNF148's function in NSCLC, subsequent functional studies included CCK-8, colony formation, and Transwell, along with glycolysis assays. Student’s T-test was conducted for data analysis with GraphPad Prism 9.0.

Results: The expression of PFKP in NSCLC was increased, and it was linked to worse outcomes. This increased expression of PFKP in NSCLC was induced by ZNF148. Silencing ZNF148 remarkably dampened NSCLC cell proliferation, invasion, and glycolysis capacities. According to a mechanistic study, ZNF148 regulates the PFKP/PD-L1 axis, which promotes NSCLC tumorigenesis.

Conclusion: It has been established that ZNF148-induced PFKP is key to the proliferation, invasion, and glycolysis abilities of NSCLC cells by regulating PD-L1 expression. Therefore, the ZNF148/PFKP/PD-L1 axis could be a potential biological signature and target for NSCLC diagnosis and treatment.

Keywords

ZNF148 / PFKP / PD-L1 / NSCLC / proliferation

References

[1] Dumonceau JM,Papanikolaou IS.Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline - updated October 2017.Endoscopy2018;50:910-30

[2] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[3] Lang L,Shay C.PFKP signaling at a glance: an emerging mediator of cancer cell metabolism. In: Guest PC, editor. Reviews on biomarker studies of metabolic and metabolism-related disorders. Cham: Springer International Publishing; 2019. pp. 243-58.

[4] Lee JH,Li J.Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis.Nat Commun2017;8:949 PMCID:PMC5643558

[5] Lee SY,Choi JE.Genetic polymorphisms in glycolytic pathway are associated with the prognosis of patients with early stage non-small cell lung cancer.Sci Rep2016;6:35603

[6] Shen J,Lv H.PFKP is highly expressed in lung cancer and regulates glucose metabolism.Cell Oncol2020;43:617-29

[7] Wang F,Zhang Z.Platelet isoform of phosphofructokinase promotes aerobic glycolysis and the progression of non-small cell lung cancer.Mol Med Rep2021;23:74 PMCID:PMC7716410

[8] Zhang CZ,Lai PB.Transcription factor ZBP-89 in cancer growth and apoptosis.Biochim Biophys Acta2010;1806:36-41

[9] Zou ZV,Lindberg M.Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway.Sci Rep2020;10:14156 PMCID:PMC7447789

[10] Nilton A,Zou ZV.Targeting Zfp148 activates p53 and reduces tumor initiation in the gut.Oncotarget2016;7:56183-92 PMCID:PMC5302905

[11] Essien BE,Ocadiz-Ruiz R.Transcription factor ZBP-89 drives a feedforward loop of β-catenin expression in colorectal cancer.Cancer Res2016;76:6877-87 PMCID:PMC5379474

[12] Liu L,Bai R,Tian Z.MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation.Oncogenesis2017;6:e318 PMCID:PMC5520497

[13] Zhou Z,Song C.circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis.J Cancer2023;14:2574-84 PMCID:PMC10475366

[14] Wang S,Lim JS,Du L.Phosphofructokinase 1 platelet isoform induces PD-L1 expression to promote glioblastoma immune evasion.Genes Genomics2022;44:1509-17

[15] Miller M.Advances in systemic therapy for non-small cell lung cancer.BMJ2021;375:n2363

[16] Oliver AL.Lung Cancer: Epidemiology and screening.Surg Clin North Am2022;102:335-44

[17] Liu P,Ou X.The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition.Mol Cancer2022;21:198 PMCID:PMC9555172

[18] Yu Z,Chen S.Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy.Drug Resist Updat2022;67:100915

[19] Zou Y,Kong Y.The single-cell landscape of intratumoral heterogeneity and the immunosuppressive microenvironment in liver and brain metastases of breast cancer.Adv Sci2023;10:e2203699 PMCID:PMC9929130

[20] Sha X,Wang F,Yang L.Silencing PFKP restrains the stemness of hepatocellular carcinoma cells.Exp Cell Res2021;407:112789

[21] Chen G,Zhang Y.Silencing PFKP inhibits starvation-induced autophagy, glycolysis, and epithelial mesenchymal transition in oral squamous cell carcinoma.Exp Cell Res2018;370:46-57

[22] Wang Y,Ai YQ.Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data.Neoplasma2015;62:966-73

[23] Vidoni C,Vallino L.Glycolysis inhibition of autophagy drives malignancy in ovarian cancer: exacerbation by IL-6 and attenuation by resveratrol.Int J Mol Sci2023;24:1723 PMCID:PMC9866176

[24] Savio M,Corpina C.Resveratrol and its analogue 4,4′-dihydroxy-trans-stilbene inhibit lewis lung carcinoma growth in vivo through apoptosis, autophagy and modulation of the tumour microenvironment in a murine model.Biomedicines2022;10:1784 PMCID:PMC9332680

[25] Chen J,Lu G.PFKP alleviates glucose starvation-induced metabolic stress in lung cancer cells via AMPK-ACC2 dependent fatty acid oxidation.Cell Discov2022;8:52 PMCID:PMC9156709

[26] Zhang L,Min S.Hyperbaric oxygen therapy represses the warburg effect and epithelial-mesenchymal transition in hypoxic NSCLC cells via the HIF-1α/PFKP axis.Front Oncol2021;11:691762 PMCID:PMC8335162

[27] Yan SM,He F.High expression of zinc-binding protein-89 predicts decreased survival in esophageal squamous cell cancer.Ann Thorac Surg2014;97:1966-73

[28] Gao X,Sun X.Upregulation of ZNF148 in SDHB-deficient gastrointestinal stromal tumor potentiates Forkhead box M1-mediated transcription and promotes tumor cell invasion.Cancer Sci2020;111:1266-78 PMCID:PMC7156819

[29] Cai MY,Li YH.High-expression of ZBP-89 correlates with distal metastasis and poor prognosis of patients in clear cell renal cell carcinoma.Biochem Biophys Res Commun2012;426:636-42

[30] Gao X,Wu Y.Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia.J Clin Invest2021;131:e143119 PMCID:PMC8363288

[31] Huang X,Wang H.PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a.J Exp Clin Cancer Res2017;36:129 PMCID:PMC5602941

[32] Dai Z,Liu G.Identification of clinical and tumor microenvironment characteristics of hypoxia-related risk signature in lung adenocarcinoma.Front Mol Biosci2021;8:757421 PMCID:PMC8634728