{"entity": "publication", "iuid": "6bb9e609167c401596379aee7503cc92", "timestamp": "2026-09-25T23:03:31.919Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/6bb9e609167c401596379aee7503cc92.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/6bb9e609167c401596379aee7503cc92"}}, "title": "\u0394Np63 bookmarks and creates an accessible epigenetic environment for TGF\u03b2-induced cancer cell stemness and invasiveness.", "authors": [{"family": "Vasilaki", "given": "Eleftheria", "initials": "E"}, {"family": "Bai", "given": "Yu", "initials": "Y"}, {"family": "Ali", "given": "Mohamad Moustafa", "initials": "MM"}, {"family": "Sundqvist", "given": "Anders", "initials": "A"}, {"family": "Moustakas", "given": "Aristidis", "initials": "A"}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH"}], "type": "journal article", "published": "2024-08-23", "journal": {"title": "Cell Commun. Signal", "issn": "1478-811X", "volume": "22", "issue": "1", "pages": "411", "issn-l": "1478-811X"}, "abstract": "p63 is a transcription factor with intrinsic pioneer factor activity and pleiotropic functions. Transforming growth factor \u03b2 (TGF\u03b2) signaling via activation and cooperative action of canonical, SMAD, and non-canonical, MAP-kinase (MAPK) pathways, elicits both anti- and pro-tumorigenic properties, including cell stemness and invasiveness. TGF\u03b2 activates the \u0394Np63 transcriptional program in cancer cells; however, the link between TGF\u03b2 and p63 in unmasking the epigenetic landscape during tumor progression allowing chromatin accessibility and gene transcription, is not yet reported.\n\nSmall molecule inhibitors, including protein kinase inhibitors and RNA-silencing, provided loss of function analyses. Sphere formation assays in cancer cells, chromatin immunoprecipitation and mRNA expression assays were utilized in order to gain mechanistic evidence. Mass spectrometry analysis coupled to co-immunoprecipitation assays revealed novel p63 interactors and their involvement in p63-dependent transcription.\n\nThe sphere-forming capacity of breast cancer cells was enhanced upon TGF\u03b2 stimulation and significantly decreased upon \u0394Np63 depletion. Activation of TGF\u03b2 signaling via p38 MAPK signaling induced \u0394Np63 phosphorylation at Ser 66/68 resulting in stabilized \u0394Np63 protein with enhanced DNA binding properties. TGF\u03b2 stimulation altered the ratio of H3K27ac and H3K27me3 histone modification marks, pointing towards higher H3K27ac and increased p300 acetyltransferase recruitment to chromatin. By silencing the expression of \u0394Np63, the TGF\u03b2 effect on chromatin remodeling was abrogated. Inhibition of H3K27me3, revealed the important role of TGF\u03b2 as the upstream signal for guiding \u0394Np63 to the TGF\u03b2/SMAD gene loci, as well as the indispensable role of \u0394Np63 in recruiting histone modifying enzymes, such as p300, to these genomic regions, regulating chromatin accessibility and gene transcription. Mechanistically, TGF\u03b2 through SMAD activation induced dissociation of \u0394Np63 from NURD or NCOR/SMRT histone deacetylation complexes, while promoted the assembly of \u0394Np63-p300 complexes, affecting the levels of histone acetylation and the outcome of \u0394Np63-dependent transcription.\n\n\u0394Np63, phosphorylated and recruited by TGF\u03b2 to the TGF\u03b2/SMAD/\u0394Np63 gene loci, promotes chromatin accessibility and transcription of target genes related to stemness and cell invasion.", "doi": "10.1186/s12964-024-01794-5", "pmid": "39180088", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11342681"}, {"db": "pii", "key": "10.1186/s12964-024-01794-5"}], "notes": [], "created": "2026-09-23T12:27:03.785Z", "modified": "2026-09-23T12:27:03.801Z"}