ArticleClinical epigenetics2025
Identification of methylation-related genes and the potential regulatory mechanism of SLAMF6 in CMS4 colorectal cancer.
Article in Clinical epigenetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- SLAMF6 Enhances the Efficacy of Anti-PD-L1 Immunotherapy in CRC Through the STAT1/CXCL10 Signaling Axis.Cancer science · 2026Article
- Integrated single-cell and machine learning analysis identifies PMAIP1 as a novel biomarker for predicting prognosis and immunotherapy response in colorectal cancer.Scientific reports · 2025Article
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6 authors.
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Abstract
backgroundsConsensus molecular subtype 4 (CMS4) of colorectal cancer (CRC) is characterized by TGF-β activation, and generally accompanied with metastasis and recurrence. Nevertheless, molecular biomarkers and regulatory mechanisms underlying CMS4 CRC remain elusive. This study investigated methylation sites in CMS4 CRC and explored the mechanistic role of SLAMF6 in CRC.
methodsRandom forest and LASSO regression identified significant methylation sites, and Kaplan Meier analysis pinpointed prognosis-related sites. The mRNA and protein expression levels of SLAMF6 were identified by qPCR, western blot, immunohistochemistry and public database. Bisulfite sequencing PCR and methylation specific PCR were employed to validate SLAMF6 promoter methylation. Western blot was applied to study the specific mechanism underlying TGF-β regulating SLAMF6 methylation. Chromatin immunoprecipitation and electrophoretic mobility shift assay were conducted to evaluate the relationship between SMAD3 and DNMT1. The anti-tumor effect of methyltransferase inhibitor (5-Aza) and PD-L1 antibody was assessed in tumor bearing mice.
resultsWe detected 726 differentially methylated sites between CMS4 and CMS1-3 subtypes (p < 0.05), with CMS4 showing prominently elevated methylation. Machine learning approaches refined to 43 methylation sites and 8 methylation sites were involved with significant prognostic value. The methylation level of SLAMF6 in CMS4 was much higher than other subtypes. Diminished SLAMF6 expression was firstly authenticated in CRC compared with normal colon tissues. It was more emphatic in CRC with metastasis and related with worse prognosis. Mechanically, p-SMAD2/3 and DNMT1 were acknowledged as the downstream effector of TGF-β activation. Next, p-SMAD3 was demonstrated to bound to DNMT1 promoter inducing SLAMF6 hypermethylation. Most interestingly, SLAMF6 was positively correlated with multiple immune cells and the combination of 5-Aza and PD-L1 antibody impeded tumor growth and upregulated CD8
conclusionsTogether, our study illustrated a novel epigenetic mechanism mediated by TGF-β/SMAD3/DNMT1, and suggested a potential target for CRC prognosis and immunotherapy.
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