Phosphorylation of serines 287/288 in DEK regulates cell-type-specific chromatin occupancy and compaction [ChIP-Seq]

The conserved multifunctional chromatin modulator and oncogene DEK exhibits context-dependent genomic binding and function, but how these activities are regulated in cancer remains poorly understood. Using multi-omics and biochemical approaches, we find that while DEK predominantly occupies promoter-proximal regions in HeLa cells and primary melanocytes, its chromatin binding is dramatically reduced in melanoma cell lines—despite DEK overexpression. We attributed this to CK2-mediated phosphorylation, which governs DEK chromatin association and transcriptional output in a cell-type-specific manner. Phosphoproteomics identified 34 phosphorylation sites, including S287 and S288 within the DEK C-terminal DNA-binding domain. Strikingly, CK2 inhibition and concomitant loss of phosphorylation at S287/S288 triggered DEK redistribution to promoter regions, coinciding with transcriptional repression of oncogenic pathways and global chromatin compaction. Melanoma subtypes showed divergent responses: NRAS-mutant cells displayed dynamic, phosphorylation-dependent DEK redistribution, whereas BRAF-mutant cells lacked detectable DEK binding. Our work establishes DEK as a phosphorylation-sensitive regulator of chromatin states, with CK2-mediated modification orchestrating its tumor-specific regulatory functions. These findings nominate phospho-DEK as a potential biomarker and therapeutic target in melanoma and possibly other cancers.