CTCF/STK38 axis drives tumor progression via the Wnt/β-catenin and Hippo pathways

Metastasis remains the primary driver of cancer-related mortality; therefore, deeper mechanistic insights are needed to develop effective therapeutic strategies. Cutaneous melanoma (SKCM), the most aggressive skin malignancy with increasing incidence worldwide, exemplifies this clinical challenge. Through multiomics analysis of melanoma datasets, we identify serine/threonine kinase 38 (STK38) as a critical mediator of tumor metastasis. Elevated STK38 expression correlates strongly with metastatic progression and reduced survival in melanoma patients. Functional studies demonstrate that STK38 not only regulates cell proliferation and autophagy but also drives migration and epithelial-mesenchymal transition by sensitizing melanoma cells to tumor microenvironmental cues. Transcriptomic profiling reveals that STK38 drives tumor metastasis via the Wnt/β-catenin and Hippo signaling pathways. Mechanistically, ChIP-seq data show that CCCTC-binding factor (CTCF) binds to both the promoter and the first-intron enhancer of STK38. Disruption of these CTCF binding sites via the CRISPR/Cas9 system abolishes chromatin loop formation, suppresses promoter-enhancer functional connectivity, and downregulates STK38 expression. Our findings identify STK38 as a metastasis-promoting regulator in melanoma and suggest that its therapeutic targeting impedes metastatic dissemination.