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

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.