Abstract Background Resistance to immune checkpoint blockade substantially limits its clinical efficacy in head and neck squamous cell carcinoma(HNSCC). ZC3H13 is a component of the N6‐methyladenosine writer complex, but its roles in HNSCC progression and response to anti‐programmed cell death protein 1(anti‐PD‐1) therapy remain unclear. Methods The expression and clinical relevance of ZC3H13 were evaluated using clinical cohorts and publicly available transcriptomic datasets. Gain‐ and loss‐of‐function experiments were performed to determine the effects of ZC3H13 on the malignant phenotypes of HNSCC cells. An epithelial‐specific ZC3H13 conditional knockout mouse model of 4‐nitroquinoline‐1‐oxide‐induced oral tumorigenesis was used to assess tumor development and responsiveness to anti‐PD‐1 therapy. N6‐methyladenosine modification, RNA stability and functional rescue assays were conducted to investigate the underlying molecular mechanism. Results ZC3H13 was upregulated in HNSCC and was associated with poor prognosis and a limited response to anti‐PD‐1 treatment. ZC3H13 promoted the proliferation and invasion of HNSCC cells, whereas epithelial‐specific ablation of ZC3H13 suppressed oral tumorigenesis and enhanced the therapeutic efficacy of anti‐PD‐1 treatment. Mechanistically, ZC3H13 regulated the N6‐methyladenosine modification of cyclin D1(CCND1) mRNA and promoted its IGF2BP1‐dependent stabilization, thereby contributing to malignant tumor phenotypes and alterations in immunosuppressvie features. Conclusions The ZC3H13/IGF2BP1/CCND1 regulatory axis contributes to HNSCC progression and resistance to anti‐PD‐1 therapy. These findings identify ZC3H13 as a potential therapeutic target for improving the efficacy of anti‐PD‐1 treatment in HNSCC.
Wen-Qing Chen, Yun Li, Shuang Chen et al.· Clinical and Translational M...· 0 citations
AIMS
The phenotype alteration of vascular smooth muscle cells (VSMCs) is critical for vascular physiology and pathology. Transcription factors (TFs) and long non-coding RNAs (lncRNAs) play pivotal roles in the gene regulatory network underlying various biological processes, including the pathogenesis of vascular diseases. Despite the established role of MYOCD as a master TF in VSMC biology, the MYOCD-mediated lncRNA-protein regulatory network in VSMC phenotype alteration remains elusive. Here, we explored long non-coding RNAs (lncRNAs) potentially involved in MYOCD-dependent VSMC regulation.
METHODS AND RESULTS
We conducted an unbiased screening to identify key lncRNA regulators in this regulatory network using expression correlation analysis in diseased human arteries. As a result, we found that CARDINAL, a VSMC-enriched lncRNA located upstream of MYOCD, exhibiting a strong positive expression correlation with MYOCD. Decreased CARDINAL expression was observed in atherosclerosis in both human and mouse models. Loss of CARDINAL induced phenotypic modulation in human VSMCs and promoted injury-induced neointima formation in mice. Gain-of-function of CARDINAL drove human VSMCs towards a contractile phenotype by activating MYOCD expression in a cis-regulatory manner. Mechanistically, CARDINAL recruited the ATAC histone acetyltransferase complex to the MYOCD promoter by interacting with the histone reader ZZZ3. Subsequently, the complex increased histone acetylation at H3K4 and H3K9, thus activating the MYOCD promoter. Consequently, CARDINAL upregulated the expression of MYOCD and downstream contractile-related genes.
CONCLUSION
These findings unveil the importance of CARDINAL as a key lncRNA regulator of VSMC phenotype alteration and highlight its potential as an RNA target for therapeutic application in vascular diseases.
