PHF20 is a multidomain epigenetic reader and component of the MOF-NSL histone acetyltransferase complex that regulates transcription through recognition of methylated histones and p53. As a methyllysine-binding protein, PHF20 contains a plant homeodomain (PHD) finger that recognizes dimethylated histone H3 lysine 4 (H3K4me2) 1, and a Tudor domain that binds dimethylated p53 at lysines 370 and 382 2. These reader functions couple histone acetylation with p53 stabilization; PHF20 binding to methylated p53 reduces Mdm2-mediated degradation and promotes p53 activation 2. PHF20 also regulates autophagy genes through H3K36me2-dependent enhancer activation 3. Functionally, PHF20 controls stemness in neuroblastoma by collaborating with PARP1 to activate SOX2 and OCT4 expression 4, and regulates glioblastoma progression through MAPK and p53 signaling pathways 5. PHF20 phosphorylation by PKB modulates its p53-regulatory function during DNA damage responses 6. Clinically, PHF20 expression correlates inversely with cancer aggressiveness; high PHF20 associates with better prognosis in non-small cell lung cancer and reduced tumor grade in glioblastoma 75, positioning PHF20 as both a prognostic biomarker and potential therapeutic target.