{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:38:44Z","timestamp":1785411524769,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T00:00:00Z","timestamp":1783209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260493"],"award-info":[{"award-number":["82260493"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32300465"],"award-info":[{"award-number":["32300465"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82260493"],"award-info":[{"award-number":["82260493"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["32300465"],"award-info":[{"award-number":["32300465"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases","award":["XJDFB2024G02"],"award-info":[{"award-number":["XJDFB2024G02"]}]},{"name":"Open Research Fund Project of Key Laboratory of High Incidence Disease Research in Xinjiang, Ministry of Education","award":["2025B02"],"award-info":[{"award-number":["2025B02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine\/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A\/m5C\/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer.<\/jats:p>","DOI":"10.3390\/ijms27136040","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:43:14Z","timestamp":1783345394000},"page":"6040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of ULK3 in Cancer Progression: A Pan-Cancer Bioinformatics Analysis Integrated with Experimental Validation in Prostate Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9284-5530","authenticated-orcid":false,"given":"Yangyang","family":"Han","sequence":"first","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"},{"name":"Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi 830017, China"},{"name":"Key Laboratory of High Incidence Disease Research in Xingjiang, Xinjiang Medical University, Ministry of Education, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mannizire","family":"Rehemujiang","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xintong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niuniu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayshamgul","family":"Hasim","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi 830017, China"},{"name":"Department of Basic Medicine, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-9266","authenticated-orcid":false,"given":"Mengjia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China"},{"name":"Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Roszkowska, M. (2024). Multilevel Mechanisms of Cancer Drug Resistance. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212402"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117692","DOI":"10.1016\/j.bcp.2026.117692","article-title":"Modulating UNC-51-like Kinase 1 (ULK1) to Treat Diseases: A Perspective from Autophagic Initiator to Druggable Target","volume":"246","author":"Qi","year":"2026","journal-title":"Biochem. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.tibs.2024.03.004","article-title":"ULK\/Atg1: Phasing in and out of Autophagy","volume":"49","author":"Wang","year":"2024","journal-title":"Trends Biochem. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1038\/s12276-025-01590-2","article-title":"ULK1 Knockout Suppresses Pancreatic Cancer Progression by Inhibiting Autophagy and Enhancing Antitumor Immunity","volume":"57","author":"Jeong","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1038\/s41388-026-03702-2","article-title":"ULK1 Promotes Metastatic Progression in Experimental Models of Epithelial Ovarian Cancer","volume":"45","author":"Webb","year":"2026","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1080\/15548627.2023.2300916","article-title":"An Autophagy-Independent Role of ULK1\/ULK2 in Mechanotransduction and Breast Cancer Cell Migration","volume":"20","author":"Liang","year":"2024","journal-title":"Autophagy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10120-021-01250-0","article-title":"Methylation Silencing of ULK2 via Epithelial-Mesenchymal Transition Causes Transformation to Poorly Differentiated Gastric Cancers","volume":"25","author":"Motoo","year":"2022","journal-title":"Gastric Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/s41467-023-36410-6","article-title":"The ULK3 Kinase Is a Determinant of Keratinocyte Self-Renewal and Tumorigenesis Targeting the Arginine Methylome","volume":"14","author":"Goruppi","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s42003-025-08046-3","article-title":"Genetic Associations of Plasma Proteins and Breast Cancer Identify Potential Therapeutic Drug Candidates","volume":"8","author":"Quan","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1080\/15548627.2024.2393932","article-title":"BIN1 Deficiency Enhances ULK3-Dependent Autophagic Flux and Reduces Dendritic Size in Mouse Hippocampal Neurons","volume":"21","author":"Jin","year":"2025","journal-title":"Autophagy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s12943-024-02069-w","article-title":"Cancer, Metastasis, and the Epigenome","volume":"23","author":"Kiri","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/cbin.11741","article-title":"FKBP1A Upregulation Correlates with Poor Prognosis and Increased Metastatic Potential of HNSCC","volume":"46","author":"Patel","year":"2022","journal-title":"Cell Biol. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6588","DOI":"10.21037\/tcr-2025-989","article-title":"Bioinformatics Analysis Identifies ULK3 as a Novel Prognostic and Immune-Related Biomarker in Esophageal Cancer","volume":"14","author":"Cui","year":"2025","journal-title":"Transl. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.7150\/thno.39341","article-title":"Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer","volume":"10","author":"Wu","year":"2020","journal-title":"Theranostics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41586-020-03064-z","article-title":"Chromothripsis Drives the Evolution of Gene Amplification in Cancer","volume":"591","author":"Shoshani","year":"2021","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/ng.3173","article-title":"Gene Expression Analysis Identifies Global Gene Dosage Sensitivity in Cancer","volume":"47","author":"Fehrmann","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5456","DOI":"10.1021\/acs.biochem.8b00356","article-title":"Characterization of Protein Kinase ULK3 Regulation by Phosphorylation and Inhibition by Small Molecule SU6668","volume":"57","author":"Kasak","year":"2018","journal-title":"Biochemistry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/B978-0-12-394622-5.00005-5","article-title":"Mammalian Homologues of Drosophila Fused Kinase","volume":"Volume 88","author":"Maloverjan","year":"2012","journal-title":"Vitamins & Hormones"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1042\/BCJ20210257","article-title":"Conformational Plasticity of the ULK3 Kinase Domain","volume":"478","author":"Mathea","year":"2021","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1021\/acssynbio.2c00162","article-title":"Directed Evolution of (R)-2-Hydroxyglutarate Dehydrogenase Improves 2-Oxoadipate Reduction by 2 Orders of Magnitude","volume":"11","author":"Scrima","year":"2022","journal-title":"ACS Synth. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"104859","DOI":"10.1016\/j.ebiom.2023.104859","article-title":"Identifying Actionable Druggable Targets for Breast Cancer: Mendelian Randomization and Population-Based Analyses","volume":"98","author":"Zhang","year":"2023","journal-title":"eBioMedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10615","DOI":"10.1038\/s41467-025-64336-8","article-title":"Integrating Whole Genome and Transcriptome Sequencing to Characterize the Genetic Architecture of Isoform Variation","volume":"16","author":"Liu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41568-022-00541-7","article-title":"RNA Splicing Dysregulation and the Hallmarks of Cancer","volume":"23","author":"Bradley","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"ref_24","first-page":"100210","article-title":"Mitochondria-Targeted Magnolol Inhibits OXPHOS, Proliferation, and Tumor Growth via Modulation of Energetics and Autophagy in Melanoma Cells","volume":"25","author":"Cheng","year":"2020","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.2147\/DMSO.S527411","article-title":"Role of Myeloid-Derived Suppressor Cells (MDSCs), Specifically Monocyte-Derived MDSCs, in Type 2 Diabetes-Related Diabetic Retinopathy","volume":"18","author":"Xiang","year":"2025","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s42003-022-04102-4","article-title":"Reprogramming of Pancreatic Adenocarcinoma Immunosurveillance by a Microbial Probiotic Siderophore","volume":"5","author":"Chaib","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100336","DOI":"10.1016\/j.esmoop.2021.100336","article-title":"Real-World Application of Tumor Mutational Burden-High (TMB-High) and Microsatellite Instability (MSI) Confirms Their Utility as Immunotherapy Biomarkers","volume":"7","author":"Palmeri","year":"2022","journal-title":"ESMO Open"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W509","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":"ref_29","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive Analyses of Tumor Immunity: Implications for Cancer Immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"UALCAN: An Update to the Integrated Cancer Data Analysis Platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D1340","DOI":"10.1093\/nar\/gkab851","article-title":"OncoSplicing: An Updated Database for Clinically Relevant Alternative Splicing in 33 Human Cancers","volume":"50","author":"Zhang","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The Immune Landscape of Cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.1093\/bioinformatics\/btz210","article-title":"TISIDB: An Integrated Repository Portal for Tumor-Immune System Interactions","volume":"35","author":"Ru","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network, Weinstein, J.N., Collisson, E.A., Mills, G.B., Shaw, K.R.M., Ozenberger, B.A., Ellrott, K., Shmulevich, I., Sander, C., and Stuart, J.M. (2013). The Cancer Genome Atlas Pan-Cancer Analysis Project. Nat. Genet., 45, 1113\u20131120.","DOI":"10.1038\/ng.2764"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1089\/bio.2015.29031.hmm","article-title":"The Genotype-Tissue Expression (GTEx) Project","volume":"13","author":"Carithers","year":"2015","journal-title":"Biopreserv. Biobank."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e27633","DOI":"10.2196\/27633","article-title":"Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation","volume":"23","year":"2021","journal-title":"J. Med. Internet Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1002\/imt2.238","article-title":"Sangerbox 2: Enhanced Functionalities and Update for a Comprehensive Clinical Bioinformatics Data Analysis Platform","volume":"3","author":"Chen","year":"2024","journal-title":"iMeta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An Enhanced Web Server for Large-Scale Expression Profiling and Interactive Analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D1391","DOI":"10.1093\/nar\/gkab804","article-title":"TISMO: Syngeneic Mouse Tumor Database to Model Tumor Immunity and Immunotherapy Response","volume":"50","author":"Zeng","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"bbac129","DOI":"10.1093\/bib\/bbac129","article-title":"CAMOIP: A Web Server for Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-Cancer","volume":"23","author":"Lin","year":"2022","journal-title":"Brief. Bioinform."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Shank avaram, U.T., Varma, S., Kane, D., Sunshine, M., Chary, K.K., Reinhold, W.C., Pommier, Y., and Weinstein, J.N. (2009). CellMiner: A Relational Database and Query Tool for the NCI-60 Cancer Cell Lines. BMC Genom., 10.","DOI":"10.1186\/1471-2164-10-277"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/6040\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:59:51Z","timestamp":1783346391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/6040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,5]]},"references-count":44,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27136040"],"URL":"https:\/\/doi.org\/10.3390\/ijms27136040","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,5]]}}}