SMYD3–CDCP1 Axis Drives EMT and CAF Activation in Colorectal Cancer and Is Targetable for Oxaliplatin Sensitization

<b>Background</b>: Colorectal cancer (CRC) mortality is predominantly driven by liver metastasis and poor responsiveness to chemotherapy. The histone methyltransferase SMYD3 has been implicated in oncogenic transcriptional programs; however, its downstream effectors and microenvironmental roles in CRC remain unclear. <b>Methods</b>: We investigated whether SMYD3 regulates the transcription and function of the membrane receptor CDCP1, which mediates Src/PKCδ signaling and promotes invasion and stromal remodeling. A combination of molecular assays, including ChIP-qPCR, Western blotting, and co-culture experiments, was employed to examine the SMYD3-CDCP1 axis and its impact on epithelial-mesenchymal transition (EMT), cancer-associated fibroblast (CAF) activation, and oxaliplatin (OXA) sensitivity. Results: SMYD3 directly bound to the CDCP1 promoter and catalyzed H3K4me3 enrichment, thereby enhancing CDCP1 transcription. Upregulated CDCP1 activated Src/PKCδ signaling, facilitating EMT and CAF activation within the tumor microenvironment. Genetic suppression of SMYD3 reduced metastatic potential and improved oxaliplatin response in vivo, while genetic or pharmacologic perturbation attenuated tumor-stroma crosstalk and enhanced oxaliplatin sensitivity in vitro. <b>Conclusions</b>: The SMYD3-CDCP1 axis drives CRC progression by epigenetically promoting CDCP1 transcription and remodeling the tumor microenvironment. Targeting this pathway may provide a promising therapeutic strategy to restrain metastasis and enhance chemotherapy efficacy in CRC.