PHF19 (PHD finger protein 19) is a polycomb group protein that functions as an H3K36me3 reader and PRC2 complex recruiter, playing critical roles in epigenetic gene regulation. Mechanistically, PHF19 binds histone H3 trimethylated at lysine 36 (H3K36me3) and recruits the PRC2 complex to enhance H3K27me3 methylation activity, facilitating the transition from active to repressed chr9 states 1. In embryonic stem cells, PHF19 recruits histone demethylases (RIOX1/KDM2B) to remove H3K36me3 marks, enabling PRC2-mediated H3K27me3 deposition and de novo gene silencing 2. PHF19 dysregulation is implicated in multiple malignancies: elevated PHF19 expression drives colorectal cancer tumorigenesis via super-enhancer activation 3, associates with relapsed/refractory multiple myeloma and poor prognosis 4, and promotes glioma cell proliferation through EZH2 hyperactivation 5. In prostate cancer, PHF19 long isoform (PHF19L) forms m6A-dependent condensates with YTHDC1 that paradoxically switch EZH2 function from gene suppression to activation, promoting cancer progression and therapy resistance 6. Additionally, PHF19 promotes cardiac hypertrophy by epigenetically repressing SIRT2 7 and regulates melanoma phenotype switching between proliferative and invasive states via Akt signaling 8. These findings establish PHF19 as a multifunctional epigenetic regulator with significant disease relevance across solid and hematological malignancies.