Findings identify NTMT1 as a candidate regulatory node associated with MYC activation and downstream HLA-A suppression, warranting further mechanistic and in-vivo investigation, and highlighting NTMT1 as a promising candidate for future therapeutic investigation.
Abstract
Background Identifying upstream molecular regulators linking tumor proliferation with immune-related alterations remains an important challenge in cancer therapy. NTMT1 (METTL11A), a protein N-terminal methyltransferase, has been implicated in tumorigenesis; however, its role in coordinating tumor–immune interaction is poorly understood. Methods We performed integrative single-cell RNA sequencing (GSE208653) and spatial transcriptomics (GSE208654) analyses to characterize NTMT1 expression and function in cervical cancer. Spatial deconvolution and microenvironmental co-localization analyses were used to define context-specific effects. Functional validation was conducted using RT–qPCR, Western blotting, multiplex immunofluorescence, and flow cytometry-based assays. Results NTMT1 exhibited heterogeneous expression across epithelial and immune cell populations, with enrichment in squamous cell carcinoma. Spatial transcriptomics revealed that NTMT1-positive regions were associated with altered immune composition, including reduced macrophage and increased NK/T cell infiltration. In epithelial-enriched regions, NTMT1 expression correlated with activation of cell cycle pathways, including MYC, E2F1, CDK1, and CCNB1. Functional experiments demonstrated that NTMT1 promotes cell cycle progression via MYC upregulation. In epithelial–NK/T co-localization niches, NTMT1 was associated with modulation of antigen presentation pathways and suppression of HLA-A expression. Functionally, NTMT1 overexpression reduced IFN-γ production by CD8+ T cells under the co-culture conditions used in this study, which was partially restored by HLA-A re-expression. Conclusion NTMT1 was identified as a candidate regulator associated with MYC activation and HLA-A suppression. Although the precise molecular mechanism remains to be elucidated, functional experiments demonstrated that NTMT1 overexpression was accompanied by increased MYC expression, reduced HLA-A expression, enhanced cell-cycle progression, and impaired CD8+ T-cell function. These findings identify NTMT1 as a candidate regulatory node associated with MYC activation and downstream HLA-A suppression, warranting further mechanistic and in-vivo investigation, highlighting NTMT1 as a promising candidate for future therapeutic investigation. Further in vivo studies will be required to determine its suitability as a target for combination immunotherapy.
Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is associated with substantial global mortality. Nuclear receptor coactivator 5 (NCOA5) has been implicated in several malignancies; however, its functional role and regulatory mechanisms in LUAD remain largely unknown. In this study, NCOA5 expression was evaluated in 94 paired LUAD and adjacent tissues using immunohistochemistry, RT-PCR, and Western blotting. Functional analyses were conducted using shRNA knockdown, CRISPR-mediated knockout, and overexpression models to assess the effects of NCOA5 on LUAD cell proliferation, migration, invasion, apoptosis, cell cycle progression, and organoid formation. Xenograft models were used to validate tumorigenicity in vivo. IP-MS and co-immunoprecipitation identified NCOA5-interacting proteins, while ChIP-seq and dual-luciferase assays interrogated downstream transcriptional regulation. NCOA5 was significantly upregulated in LUAD tissues and associated with advanced stage, poor differentiation, and reduced overall survival, serving as an independent prognostic factor (
P
< .040). NCOA5 knockdown inhibited LUAD cell proliferation, migration, invasion, induced G0/G1 arrest, promoted apoptosis, reduced organoid formation, and suppressed xenograft growth, whereas NCOA5 overexpression produced the opposite effects. Among 39 candidate interacting proteins identified by IP-MS, ZCCHC3 was validated as a direct NCOA5-binding partner. ZCCHC3 depletion phenocopied NCOA5 loss and reversed NCOA5-induced proliferation, migration, invasion, and colony formation, supporting a functional NCOA5–ZCCHC3 interaction. ChIP-seq analysis identified fibroblast growth factor 22 (FGF22) as a direct transcriptional target of NCOA5. FGF22 was markedly downregulated in LUAD tissues and higher FGF22 expression was associated with improved patient survival. NCOA5 suppressed FGF22 transcription, while NCOA5 inhibition increased FGF22 expression. Functionally, FGF22 knockdown enhanced LUAD aggressiveness, whereas FGF22 restoration abrogated the oncogenic effects of NCOA5 in vitro and in vivo. Collectively, these findings identify a previously unrecognized NCOA5–ZCCHC3/FGF22 axis that drives LUAD progression and provide new mechanistic insight into the role of NCOA5 in LUAD biology.
Yiran Yu, Wen Jin, Erdun Chaogetu et al.· Cell Death & Disease· 0 citations
Objective Chromosomal instability (CIN) drives genomic structural variants (such as amplifications and deletions) and promotes tumor progression. Long noncoding RNAs are known to participate in key biological processes and CIN regulation. Our previous study demonstrated that the highly expressed lncTRDMT1–5 serves as a novel prognostic biomarker in breast cancer; however, its underlying mechanisms require further investigation. Methods LncTRDMT1–5 expression was knocked down in MDA-MB-231 cells, followed by chromosomal microarray analysis (CMA). Expression levels of lncTRDMT1–5 were examined in breast cancer cells and tissues via RT-PCR. Chromatin immunoprecipitation was used to detect H3K27 acetylation in the promoter region. RNA pull-down was performed to identified interactions with the MSRB3 protein. Cell proliferation was evaluated by EdU assay, DNA damage was assessed by γH2AX immunofluorescence, and cell cycle distribution was analyzed by flow cytometry. EMT-related protein expression and cell cycle regulators were examined by western blotting. Results LncTRDMT1–5 was significantly upregulated in breast cancer cells and tissues, with H3K27 acetylation detected in its promoter. Downregulation of lncTRDMT1–5 induced CNVs across different chromosomes. Overexpression of lncTRDMT1–5 promoted cell proliferation, DNA damage, and EMT-related protein expression. RNA pulldown confirmed the relationship between lncTRDMT1–5 and MSRB3 protein. Mechanistically, lncTRDMT1–5 regulated cell cycle arrest by inhibiting p53 and inducing the expression of cell-division cycle protein 20 homologue (CDC20). Conclusion Overexpression of lncTRDMT1–5 in breast cancer induces CIN and tumor progression by promoting EMT process and increasing MSRB3, p53 and CDC20 protein expression. Targeting this molecular pathway may offer novel therapeutic strategies and improve prognostic evaluations.
Qi Chen, Yunpeng Chen, Hui Yang et al.· Frontiers in Oncology· 0 citations
Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes.
Li-Chun Wang, Bin Guo, Xue-Ping Jiao et al.· Current Gene Therapy· 0 citations
C17orf75 plays an important role in LIHC progression by regulating cell cycle progression and EMT, and it may serve as a potential therapeutic target for LIHC.
Hao Liang, Nan-Bin Liu, Yibing Melody Zhai et al.· Frontiers in Immunology· 0 citations
Background WD Repeat Domain 76 (WDR76) plays a potential role in cellular regulation; however, its comprehensive landscape across human malignancies and its specific biological function in hepatocellular carcinoma (HCC) remain largely unexplored. Methods We conducted a systematic pan-cancer analysis utilizing multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) atabases to evaluate WDR76 expression, subcellular localization, and its correlation with clinicopathologic features, genomic instability, and immune infiltration. Diagnostic and prognostic values were assessed via Receiver operating characteristic (ROC) and Kaplan-Meier analyses. Furthermore, the functional role of WDR76 in HCC was validated in vitro using Hep-3B and Huh7 cell lines through siRNA-mediated knockdown, followed by CCK-8, wound-healing, and transwell assays. Results WDR76 was significantly upregulated in the majority of tumor types, including LIHC, LUAD, and COAD, while exhibiting nuclear localization. Elevated WDR76 expression correlated with advanced tumor staging, metastasis, and poor clinical outcomes across multiple cohorts, particularly in ACC, KIRP, and LIHC. ROC analysis highlighted its exceptional diagnostic precision in cancers such as GBM and LIHC. Immunologically, WDR76 expression was intricately linked to immune cell infiltration, immune checkpoint markers, and genomic instability parameters, suggesting a role in shaping the tumor microenvironment. Drug sensitivity profiling revealed that high WDR76 levels correlate with resistance to specific chemotherapeutic agents. Experimentally, silencing WDR76 in HCC cells significantly suppressed cell proliferation, migration, and invasion capabilities. Conclusion Our study establishes WDR76 as a robust pan-cancer prognostic biomarker and a potential immunotherapeutic target. Specifically, we provide experimental evidence that WDR76 functions as an oncogenic driver in liver cancer, promoting malignant phenotypes and offering a novel avenue for targeted therapeutic intervention.
Yi-Fan Wang, Rong Zhou, Shen-Long Guo et al.· International Journal of Imm...· 0 citations
RNA sequencing of DRM-treated versus control rat C6 glioma cells identified 3747 differentially expressed genes, including 1660 upregulated and 2087 downregulated genes, with thrombospondin-1 markedly downregulated after DRM treatment, which may contribute to the anti-invasive effects of DRM.
Hefei Liu, Hong-Sheng Liang, Liwei Wang et al.· International Journal of Bio...· 0 citations
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