{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T07:25:53Z","timestamp":1764833153849,"version":"3.46.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Skin cutaneous melanoma (SKCM) is extremely malignant, leading to poor prognosis. Epigenetic dysregulation, particularly histone modifications, contributes to disease progression. However, effective histone-based prognostic biomarkers are still lacking in clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptomic data from TCGA-SKCM and five GEO datasets were analyzed. Ten machine learning algorithms were integrated to build 101 prognostic models. The optimal model, based on seven histone-related genes, showed the highest C-index and was validated in both training and validation cohorts. WDR77 was identified as the hub gene by random forest analysis. The expression of WDR77 was profiled in SKCM. Survival analysis, pathway enrichment analyses, single-cell and spatial transcriptomics were performed to investigate the role of WDR77 in SKCM. The therapeutic relevance of WDR77 was also investigated. In vitro experiments were conducted to validate the function of WDR77.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>WDR77, a histone methylation factor working with PRMT5, was identified as a key candidate. WDR77 was significantly upregulated in SKCM and correlated with poor clinical outcomes. Pathway analysis showed that WDR77 was primarily associated with cell-cycle dysregulation. CDC20, a cell cycle factor, emerged as a key co-expressed gene. Patients with concurrent high expression of WDR77 and CDC20 had the worst survival outcomes. WDR77 was predominantly expressed in malignant cells across pan-cancer datasets and positively correlated with CDC20. Spatial transcriptomics confirmed their co-localization and co-upregulation in tumor regions. Functional experiments demonstrated that WDR77 promotes proliferation, migration, and cell cycle progression. Overexpression of WDR77 also increased CDC20 protein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>WDR77 serves as both a prognostic biomarker and functional regulator in melanoma, highlighting its potential as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1611112","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:32:53Z","timestamp":1764829973000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Histone-related gene WDR77 promotes tumor progression through cell cycle regulation in skin cutaneous melanoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Haoxue","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxiu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2858","DOI":"10.1038\/s41467-020-15546-9","article-title":"Pre-clinical modeling of cutaneous melanoma","volume":"11","author":"Rebecca","year":"2020","journal-title":"Nat Commun"},{"key":"B2","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","article-title":"Global burden of cutaneous melanoma in 2020 and projections to 2040","volume":"158","author":"Arnold","year":"2022","journal-title":"JAMA Dermatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1016\/j.cell.2015.05.044","article-title":"Genomic classification of cutaneous melanoma","volume":"161","year":"2015","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"35","DOI":"10.2147\/ITT.S134842","article-title":"Melanoma treatment in review","volume":"7","author":"Domingues","year":"2018","journal-title":"Immunotargets Ther"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/ans.14921","article-title":"Management of in-transit melanoma metastases: a review","volume":"89","author":"Nan Tie","year":"2019","journal-title":"ANZ J Surg"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31559-9","article-title":"Melanoma","volume":"392","author":"SChadendorf","year":"2018","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12916-016-0571-0","article-title":"Advances in immunotherapy for melanoma","volume":"14","author":"Redman","year":"2016","journal-title":"BMC Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.4401","article-title":"Rationale for immune checkpoint inhibitors plus targeted therapy in metastatic melanoma: A review","volume":"6","author":"Dummer","year":"2020","journal-title":"JAMA Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01141-1","article-title":"A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance","volume":"23","author":"Huang","year":"2022","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06084-7","article-title":"Epigenetic dysregulation from chromosomal transit in micronuclei","volume":"619","author":"Agustinus","year":"2023","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/s41392-024-01918-w","article-title":"Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases","volume":"9","author":"Yao","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B12","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2007.02.005","article-title":"Chromatin modifications and their function","volume":"128","author":"Kouzarides","year":"2007","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00468-7","article-title":"Histone post-translational modifications - cause and consequence of genome function","volume":"23","author":"Maill\u00e1n-Zambrano","year":"2022","journal-title":"Nat Rev Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/15257770.2023.2296616","article-title":"Insights on the nuclear shuttling of H2A-H2B histone chaperones","volume":"43","author":"Kaur","year":"2024","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"B15","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.tcb.2021.07.001","article-title":"Cell cycle on the crossroad of tumorigenesis and cancer therapy","volume":"32","author":"Liu","year":"2022","journal-title":"Trends Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpt.2023.09.003","article-title":"Overlap in oncogenic and pro-inflammatory pathways associated with areca nut and nicotine exposure","volume":"2","author":"Garg","year":"2023","journal-title":"Cancer Pathog Ther"},{"key":"B17","doi-asserted-by":"publisher","first-page":"eaaz5683","DOI":"10.1126\/scitranslmed.aaz5683","article-title":"PRMT5 control of cGAS\/STING and NLRC5 pathways defines melanoma response to antitumor immunity","volume":"12","author":"Kim","year":"2020","journal-title":"Sci Transl Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/15257770.2025.2476597","article-title":"Histone chaperones as potential epidrug targets against cancer","volume":"10","author":"Malik","year":"2025","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu375","article-title":"Preserving biological heterogeneity with a permuted surrogate variable analysis for genomics batch correction","volume":"30","author":"Parker","year":"2014","journal-title":"Bioinformatics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1186\/s12859-019-3125-6","article-title":"TS-GOEA: a web tool for tissue-specific gene set enrichment analysis based on gene ontology","volume":"20","author":"Peng","year":"2019","journal-title":"BMC Bioinf"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map Hum proteome","volume":"347","author":"Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.cell.2020.05.039","article-title":"Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma","volume":"182","author":"Ji","year":"2020","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01075-3","article-title":"Super-resolved spatial transcriptomics by deep data fusion","volume":"40","author":"Bergenstr\u00e5hle","year":"2022","journal-title":"Nat Biotechnol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e1000217","DOI":"10.1371\/journal.pcbi.1000217","article-title":"Inferring pathway activity toward precise disease classification","volume":"4","author":"Lee","year":"2008","journal-title":"PloS Comput Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky939","article-title":"CancerSEA: a cancer single-cell state atlas","volume":"47","author":"Yuan","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3984","article-title":"Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells","volume":"49","author":"Meyers","year":"2017","journal-title":"Nat Genet"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac959","article-title":"TISCH2: expanded datasets and new tools for single-cell transcriptome analyses of the tumor microenvironment","volume":"51","author":"Han","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1016\/j.cell.2018.09.006","article-title":"A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade","volume":"175","author":"Jerby-Arnon","year":"2018","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00861","article-title":"Umap: Uniform manifold approximation and projection for dimension reduction","author":"McInnes","year":"2018","journal-title":"arXiv preprint arXiv:1802.03426"},{"key":"B33","doi-asserted-by":"publisher","first-page":"110671","DOI":"10.1038\/s41587-022-01448-2","article-title":"Spatial transcriptomics: Technologies, applications and experimental considerations","volume":"115","author":"Wang","year":"2023","journal-title":"Genomics"},{"key":"B34","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1038\/s41467-023-36560-7","article-title":"Reconstruction of the tumor spatial microenvironment along the Malignant-boundary-nonmalignant axis","volume":"14","author":"Xun","year":"2023","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-2650","article-title":"The web-based portal spatialTME integrates histological images with single-cell and spatial transcriptomics to explore the tumor microenvironment","volume":"84","author":"Shi","year":"2024","journal-title":"Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-0689","article-title":"TIP: A web server for resolving tumor immunophenotype profiling","volume":"78","author":"Xu","year":"2018","journal-title":"Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3047","article-title":"Improved vectors and genome-wide libraries for CRISPR screening","volume":"11","author":"Sanjana","year":"2014","journal-title":"Nat Methods"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-015-1847-9","article-title":"The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond","volume":"72","author":"Stopa","year":"2015","journal-title":"Cell Mol Life Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.205","article-title":"A TGF\u03b2-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression","volume":"36","author":"Chen","year":"2017","journal-title":"Oncogene"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e2026327118","DOI":"10.1073\/pnas.2026327118","article-title":"Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer","volume":"118","author":"Zhao","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx727","article-title":"The PRMT5\/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer","volume":"45","author":"Rengasamy","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e2400160","DOI":"10.1002\/advs.202400160","article-title":"TBL2 promotes tumorigenesis via PRMT5\/WDR77-mediated AKT activation in breast cancer","volume":"11","author":"Lu","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/mc.23693","article-title":"HNRNPC promotes estrogen receptor-positive breast cancer cell cycle by stabilizing WDR77 mRNA in an m6A-dependent manner","volume":"63","author":"Xu","year":"2024","journal-title":"Mol Carcinog"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.03.001","article-title":"APC\/C ubiquitin ligase: Functions and mechanisms in tumorigenesis","volume":"67","author":"Schrock","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2165","article-title":"How APC\/C-Cdc20 changes its substrate specificity in mitosis","volume":"13","author":"Izawa","year":"2011","journal-title":"Nat Cell Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1042\/BST0380072","article-title":"Cyclin A and Nek2A: APC\/C-Cdc20 substrates invisible to the mitotic spindle checkpoint","volume":"38","author":"van Zon","year":"2010","journal-title":"Biochem Soc Trans"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2015.04.002","article-title":"Targeting Cdc20 as a novel cancer therapeutic strategy","volume":"151","author":"Wang","year":"2015","journal-title":"Pharmacol Ther"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2022.188824","article-title":"Targeting Cdc20 for cancer therapy","volume":"1877","author":"Jeong","year":"2022","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-3956","article-title":"Germline missense variants in CDC20 result in aberrant mitotic progression and familial cancer","volume":"82","author":"Chen","year":"2022","journal-title":"Cancer Res"},{"key":"B51","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s13046-022-02363-9","article-title":"CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological Malignancies","volume":"41","author":"Bruno","year":"2022","journal-title":"J Exp Clin Cancer Res"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/s42003-023-05526-2","article-title":"Functional analysis of recurrent CDC20 promoter variants in human melanoma","volume":"6","author":"Godoy","year":"2023","journal-title":"Commun Biol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c01444","article-title":"Discovery of cdc20\/hsp90 dual-target inhibitors with potent antitumor activity for therapy of acquired resistant melanoma","volume":"68","author":"Chen","year":"2025","journal-title":"J Med Chem"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0137-z","article-title":"USP27-mediated Cyclin E stabilization drives cell cycle progression and hepatocellular tumorigenesis","volume":"37","author":"Dong","year":"2018","journal-title":"Oncogene"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09433-w","article-title":"Targeting G1-S-checkpoint-compromised cancers with cyclin A\/B RxL inhibitors","volume":"646","author":"Singh","year":"2025","journal-title":"Nature"},{"key":"B56","doi-asserted-by":"publisher","first-page":"e74710","DOI":"10.1371\/journal.pone.0074710","article-title":"PRMT5 is upregulated in Malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.)","volume":"8","author":"Nicholas","year":"2013","journal-title":"PloS One"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-332998","article-title":"Identification of PRMT5 as a therapeutic target in cholangiocarcinoma","volume":"74","author":"Elurbide","year":"2024","journal-title":"Gut"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e186052","DOI":"10.1172\/JCI186052","article-title":"C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling","volume":"135","author":"Qiao","year":"2025","journal-title":"J Clin Invest"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.2339","article-title":"First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration","volume":"35","author":"Rodon","year":"2024","journal-title":"Ann Oncol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-0092","article-title":"Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in advanced solid tumors","volume":"29","author":"Vieito","year":"2023","journal-title":"Clin Cancer Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1611112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:32:55Z","timestamp":1764829975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1611112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":60,"alternative-id":["10.3389\/fimmu.2025.1611112"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1611112","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,12,4]]},"article-number":"1611112"}}