PCGF6 is a polycomb group protein and core component of the non-canonical PRC1.6 complex that functions as both a transcriptional repressor and activator depending on cellular context. As part of PRC1-like complexes, PCGF6 mediates monoubiquitination of histone H2A at lysine 119 and modulates H3K4 methylation levels by activating the KDM5D histone demethylase, thereby maintaining transcriptionally repressive chr10 states. However, in embryonic stem cells, PCGF6 atypically acts as a positive regulator, directly activating core pluripotency factors including Oct4, Sox2, and Nanog to maintain stem cell identity 1. PCGF6 also controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression in cooperation with MYC 2. In cancer contexts, PCGF6 expression is elevated in papillary renal cell carcinoma, where it promotes proliferation and progression by facilitating MAZ/CDK4 axis expression through interactions with MAX and KDM5D that reduce promoter DNA methylation 3. PCGF6 has also been implicated in prostate cancer, with androgen-induced differential methylation patterns affecting PCGF6 expression 4. PCGF6 is associated with multiple developmental and skeletal disorders, including spondylocostal dysostosis and metaphyseal chondrodysplasias, and plays roles in male germ cell differentiation 5. The therapeutic potential of targeting the PCGF6/MAZ/CDK4 regulatory axis in renal cell carcinoma warrants further investigation.