In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression, identifying the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.
Abstract
Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.
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
Results provide experimental support for targeting the PI3K/AKT/mTOR axis as a potential therapeutic strategy in cervical cancer through functional and mechanistic link between recurrent PIK3CA-E545K-MUT and aggressive tumor behavior in cervical cancer via AKT/mTOR pathway activation.
Congxiu Huang, Wei Zhang, Xiaoyu Ma et al.· Zeitschrift für Induktive Ab...· 0 citations
BACKGROUND
Renal cell carcinoma (RCC) is a common urinary malignancy that lacks reliable early biomarkers. Although epigenetic silencing of tumor suppressor genes mediated by DNA methylation is common in RCC, the specific role and regulation of the basement membrane component COL4A4 remain unclear.
METHODS
Bulk and single-cell RNA sequencing (scRNA-seq), DNA methylation analysis, The Cancer Genome Atlas data and in-house clinical RCC cohorts were integrated to characterize COL4A4 expression, epigenetic regulation, clinical significance, and associations with tumor microenvironment (TME) features. The biological functions of COL4A4 were evaluated using in vitro functional assays and in vivo xenograft models. Mechanistic studies included 5-Aza demethylation treatment and JAK2/STAT3 pathway inhibition.
RESULTS
COL4A4 was downregulated in RCC, and its downregulation is associated with promoter hypermethylation, serving as an independent prognostic factor. Functionally, COL4A4 inhibited RCC cell proliferation, migration, and invasion in vitro, and suppressed tumor growth in vivo. Mechanistically, COL4A4 negatively modulated the JAK2/STAT3 signaling pathway. scRNA-seq revealed that COL4A4 was predominantly enriched in epithelial cells. Low COL4A4 expression is associated with altered extracellular matrix-receptor interactions and an immunosuppressive TME.
CONCLUSIONS
COL4A4 acts as a methylation-silenced RCC tumor suppressor that negatively modulates JAK2/STAT3 signaling and correlates with TME features, representing a potential epigenetic therapeutic target.
Hanxi Zhou, Xiong Tian, Zhenyu Yang et al.· International Immunopharmaco...· 0 citations
Elevated MXRA5 expression exhibited a positive correlation with advanced lymph node metastasis and impaired clinical prognosis, and its potential as a valuable prognostic biomarker and therapeutic target for managing metastatic disease is revealed.
Jian Wang, Jie Tang, Yaoxin Wang· Korean Journal of Physiology...· 0 citations
Introduction SOX2, a key pluripotency gene, plays a central role in breast cancer stem cell (BCSC) biology, driving tumor aggressiveness. Although SOX2 dysregulation has been widely studied across various cancers, its specific regulatory mechanisms in breast cancer (BC) remain incompletely elucidated. This study examined the regulatory axis of the SOX2 gene and associated molecular mechanisms underlying BCSC maintenance and prognosis. Methods This retrospective cross-sectional study analyzed breast tumor tissues and adjacent normal controls collected consecutively from two tertiary hospitals. SOX2 promoter methylation was assessed using methylation-Specific PCR, and expression of SOX2, DNMT3b, TET3, miR-200b-3p, and TGFβ1 was quantified by qPCR. Results Aberrant methylation of the SOX2 promoter, linked to increased expression, was observed in the BC cohort. Notably, several samples exhibited a poised promoter state, reflecting an epigenetic configuration associated with stemness. Upregulation of DNMT3b in miR-200b-reduced cells was significantly associated with SOX2 promoter methylation, suggesting a feedback loop modulating methylation dynamics. Additionally, a positive association between deregulated TET3 and TGFβ1 highlights a positive feedback loop in the dynamic tumor microenvironment. SOX2 methylation emerged as a strong prognostic marker, characterized by a low hazard ratio and high diagnostic sensitivity. Its combination with DNMT3b improved specificity (SE = 90%, SP = 79%). Reduced TET3 and miR200b expression correlated with poor outcomes, and their integration with SOX2 formed a tri-gene signature that enhanced patient stratification. Correlation analyses revealed coordinated expression among SOX2, TET3, and TGFβ1, supporting their role in methylome regulation. Conclusion The findings underscore the clinical significance of this axis and its embedded feedback circuits in shaping BC progression and therapeutic response.
Farhan Maqbool, A. Ahamed, Summaya Anwar et al.· Cancer Control: Journal of t...· 0 citations
Abstract Lung cancer is currently the leading cause of cancer-related deaths worldwide. Approximately 85% of lung cancer patients have non-small cell lung cancer (NSCLC), and >50% of these patients present with metastasis at their initial diagnosis. Despite advances in our understanding of lung cancer oncogenesis, the mechanism by which lung cancer becomes aggressive and leads to patient death is still poorly characterized. We found that long noncoding RNA RNA-associated with metastasis 11 (RAMS11) (LINC01564) is significantly upregulated in lung cancer patients compared to healthy patients. Here, we demonstrate that RAMS11 is critical for NSCLC tumor progression by regulating expression of NOTCH3, a key driver of tumorigenic potential. Mechanistically, RAMS11 is essential for NRF2 chromatin binding and the associated deposition of the active enhancer mark, H3K27ac, at the NOTCH3 enhancer region. Functional analysis revealed RAMS11–NRF2-dependent activation of NOTCH3 signaling enforces a tumor-initiating capacity, characterized by enhanced self-renewal capabilities and tumor initiation ability, thereby supporting malignant proliferation. Moreover, disruption of RAMS11 signaling markedly suppressed tumorigenic growth and sensitized NSCLC cells to cisplatin-induced apoptosis, uncovering a potential therapeutic vulnerability to more effectively target NSCLC patients. Collectively, these findings reveal a previously unknown role of RAMS11 in NSCLC progression and chemotherapy resistance.
Gejae G. L. Jeffers, Y. Kim, Nicole M. White et al.· NAR Cancer· 0 citations
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