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Meng Zhang

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Open access Jul 2026

The Role of ULK3 in Cancer Progression: A Pan-Cancer Bioinformatics Analysis Integrated with Experimental Validation in Prostate Cancer

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.

Yangyang Han, Meng Zhang, Mannizire Rehemujiang et al. · 0 citations
Open access Aug 2026

Tumor suppressor syntaxin binding protein 1 regulates alternative splicing of DNA repair genes related to radiation sensitivity in breast cancer cells

As the most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC) is frequently treated with radiotherapy. Downregulation of syntaxin binding protein 1 (STXBP1) gene expression is notably associated with poor prognosis in patients with breast cancer and its protein expression level is associated with tumor radioresistance. However, the precise molecular mechanisms by which STXBP1 regulates breast cancer pathogenesis and radiotherapy resistance remain to be elucidated. In the present study, STXBP1 was overexpressed in MDA-MB-231 cells to investigate its effects on cell proliferation and apoptosis. Transcriptomic sequencing (RNA-sequencing; RNA-seq) was performed to identify differentially expressed genes and alternative splicing events regulated by STXBP1. Additionally, a publicly available RNA-seq dataset (GSE189495) associated with breast cancer radiotherapy, including three fractionally irradiated 20 Gy and three age-matched control MCF-7 cell samples were analyzed to identify radiotherapy-associated alternative splicing alterations. Integrated analysis of these two datasets was conducted to explore the potential mechanisms underlying STXBP1-mediated radiotherapy response in breast cancer. Key gene expression changes and alternative splicing events were validated using reverse transcription-quantitative (RT-q) PCR. In MDA-MB-231 cells, the overexpression of STXBP1 notably inhibited cell proliferation and enhanced levels of apoptosis. Through an analysis of RNA-seq data, the present study discovered that STXBP1 regulates global gene expression and alternative splicing profiles in MDA-MB-231 cells by modulating 111 differentially expressed genes and 1,161 regulated alternative splicing events. STXBP1 plays a key role in regulating the splicing patterns of numerous DNA repair-related genes, including USP48 and PLEC. In addition, the present study conducted an overlap analysis on the transcriptome data from radiotherapy-treated MCF-7 cells alongside the dataset generated in the present study, which revealed 21 alternative splicing events associated with radiotherapy. Notably, these include the DNA repair-related gene UBE2I, and its expression pattern has been confirmed through RT-qPCR. The present study systematically delineated the downstream targets and functional mechanisms of STXBP1 in breast cancer cells, revealing its antitumor molecular role. Moreover, STXBP1 may be associated with radiation sensitivity by regulating the alternative splicing of genes associated with DNA repair. These molecular targets, such as UBE2I, hold potential as novel therapeutic avenues for breast cancer treatment, particularly for TNBC.

Meng Zhang, Xiaoxue Zhang, Qian Rou et al. · 0 citations