A non-canonical EZH2/TRIM28 epigenetic axis drives heparan sulfate remodeling and melanoma metastasis

Abstract Melanoma progression is driven not only by oncogenic alterations but also by epigenetic programs that remodel the tumor microenvironment. Heparan sulfate (HS) proteoglycans are extracellular matrix components that control growth factor signaling and cell-matrix interactions, yet how chromatin-associated factors regulate HS remodeling in cancer remains ill-defined. Here, we identify the histone methyltransferase EZH2 as a regulator of HS biosynthesis in melanoma. Bioinformatic and genomic analyses reveal enrichment of EZH2 and additional Polycomb Repressive Complex (PRC) factors at regulatory regions of HS biosynthetic genes. CRISPR-mediated loss of EZH2 modulates expression of multiple HS-modifying enzymes, notably the secreted endosulfatases SULF1 and SULF2, enhancing HS 6- O sulfation and altering ligand binding at the cell surface. Unexpectedly, EZH2 promotes SULF1 through a methyltransferase-independent, non-canonical interaction with TRIM28, whereas SULF2 is repressed through canonical PRC2 activity. Functionally, SULF1 depletion impairs melanoma cell migration and invasion and reduces spontaneous metastasis in vivo. These findings define an epigenetic axis linking chromatin regulation to glycan remodeling and identify HS-modifying enzymes as candidate targets to limit melanoma metastasis.