Comprehensive Analysis of Biologic and Prognostic Implication for ZNF536 in Pan-Cancer
Objectives: Zinc Finger Protein 536 (ZNF536) is a highly conserved zinc finger protein, acting as DNA-binding transcription suppressor, and negatively regulating neuron differentiation. However, the role of ZNF536 in cancers is still unknown.
Methods: In this study, we aim to comprehensively explore the biologic and prognostic implication of ZNF536 in pancancer by multi-layered analysis. The mRNA differential expression and DNA methylation of ZNF536 in pan-cancer and normal controls based on The Cancer Genome Atlas (TCGA) and Genotype Tissue-Expression (GTEx) data were interpreted. Immunohistochemistry was performed on a tissue micro-array to detect the protein expression of ZNF536. The prognostic implication of ZNF536 in pan-cancer was studied by survival analysis. The cBioPortal database was used to display ZNF536 genomic alterations. The co-expression of ZNF536 and immune-related genes in pan-cancer was investigated. Further research was made on the relationship between ZNF536 expression and tumor immune microenvironment. CancerSEA was employed to excavate the ZNF536 expression at single cell level with different cancer function. The biological function of ZNF536 in pan-cancer was exhibited by gene enrichment analysis.
Results: The ZNF536 mRNA was highly expressed in 4 out of 33 cancers, but lowly expressed in 22 cancers. Immunohistochemistry on the tissue micro-array confirmed the high expression of ZNF536 protein in pancreatic adenocarcinoma (PAAD) and low expression in stomach adenocarcinoma (STAD). DNA hypermethylation in prostate adenocarcinoma (PRAD) was observed, which might result in its down-regulated expression. High expression of ZNF536 predicted poor prognosis in 5 cancers, but predicted favorable prognosis in 2 cancers. Genomic alterations of ZNF536 showed mutation in 26 cancers and amplification in 20 cancers. The altered group usually had worse prognosis. ZNF536 mRNA expression was correlated with the degree of immune infiltrates in pan-cancer. Single cell sequencing and gene enrichment analysis showed that the ZNF536-correlated genes might regulate a variety of biological processes in pan-cancer, mainly via angiogenesis pathway.
Conclusion: Our results indicated that ZNF536 might be a prognostic and immune-related biomarker for specific malignancies through the angiogenesis pathway
1. Jen J, Wang YC. Zinc finger proteins in cancer progression. J Biomed Sci 2016;23:53.
2. Xia L, Lin H, Zhou Y, Lian J. ZNF750 facilitates carcinogenesis via promoting the expression of long non-coding RNA CYTOR and influences pharmacotherapy response in colon adenocarcinoma. J Zhejiang Univ Sci B 2022;23:587–96.
3. He L, Fan X, Li Y, Chen M, Cui B, Chen G, et al. Overexpression of zinc finger protein 384 (ZNF 384), a poor prognostic predictor, promotes cell growth by upregulating the expression of Cyclin D1 in Hepatocellular carcinoma. Cell Death Dis 2019;10:444.
4. Chen X, Liu C, Zhang Z, Wang M, Guo S, Li T, et al. ZNF655 Promotes the progression of glioma through transcriptional regulation of AURKA. Front Oncol 2022;12:770013.
5. Yan D, Shen M, Du Z, Cao J, Tian Y, Zeng P, et al. Developing ZNF gene signatures predicting radiosensitivity of patients with breast cancer. J Oncol 2021;2021:9255494.
6. Iraci N, Tabarrini O, Santi C, Sancineto L. NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders. Drug Discov Today 2018;23:687–95.
7. Sancineto L, Iraci N, Tabarrini O, Santi C. NCp7: targeting a multitasking protein for next-generation anti-HIV drug development part 1: covalent inhibitors. Drug Discov Today 2018;23:260–71.
8. Abbehausen C. Zinc finger domains as therapeutic targets for metal-based compounds - an update. Metallomics 2019;11:15–28.
9. Qin Z, Ren F, Xu X, Ren Y, Li H, Wang Y, et al. ZNF536, a novel zinc finger protein specifically expressed in the brain, negatively regulates neuron differentiation by repressing retinoic acid-induced gene transcription. Mol Cell Biol 2009;29:3633– 43.
10. E J, Kang Z, Yuan J, Wang Z, Tong D, Xing J. ZNF516 suppresses stem cell-like characteristics by regulating the transcription of Sox2 in colorectal cancer. Am J Cancer Res 2022;12:3745–59.
11. Li L, Liu X, He L, Yang J, Pei F, Li W, et al. ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin. Nat Commun 2017;8:691
12. Vivian J, Rao AA, Nothaft FA, Ketchum C, Armstrong J, Novak A, et al. Toil enables reproducible, open source, big biomedical data analyses. Nat Biotechnol 2017;35:314–6.
13. Thyme SB, Pieper LM, Li EH, Pandey S, Wang Y, Morris NS, et al. Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions. Cell 2019;177:478–91.e20.
14. Wang D, Guo T, Guo Q, Zhang S, Zhang J, Luo J; GeseDNA Research Team. The association between schizophrenia risk variants and creativity in healthy Han Chinese subjects. Front Psychol 2019;10:2218.
15. Lin E, Kuo PH, Liu YL, Yu YW, Yang AC, Tsai SJ. A deep learning approach for predicting antidepressant response in major depression using clinical and genetic biomarkers. Front Psychiatry 2018;9:290.
16. Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer 2020;20:303–22.
17. Huang H, Xu H, Li P, Ye X, Chen W, Chen W, et al. Zinc finger C3H1 domain-containing protein (ZFC3H1) evaluates the prognosis and treatment of prostate adenocarcinoma (PRAD): A study based on TCGA data. Bioengineered 2021;12:5504–15.
18. Yu J, Fan Z, Zhou Z, Zhang P, Bai J, Li X, et al. TP53 and LRP1B cowild predicts improved survival for patients with LUSC receiving anti-PD-L1 immunotherapy. Cancers (Basel) 2022;14:3382.
19. Shi L, Cao J, Lei X, Shi Y, Wu L. Multi-omics data identified TP53 and LRP1B as key regulatory gene related to immune phenotypes via EPCAM in HCC. Cancer Med 2022;11:2145–58.
20. Sun HY, Wei SP, Xu RC, Xu PX, Zhang WC. Sphingosine-1-phosphate induces human endothelial VEGF and MMP-2 production via transcription factor ZNF580: novel insights into angiogenesis. Biochem Biophys Res Commun 2010;395:361–6.
21. Wang X, Su B, Gao B, Zhou J, Ren XK, Guo J, et al. Cascaded bio-responsive delivery of eNOS gene and ZNF580 gene to collaboratively treat hindlimb ischemia via pro-angiogenesis and anti-inflammation. Biomater Sci 2020;8:6545–60.