Epigenetic Silencing of Primary Cilia Genes by PRAME and ETS2 in Melanoma Cells

Primary cilia are sensory organelles that regulate key signaling pathways essential for cell growth and differentiation. Loss of primary cilia is a common feature of melanoma and contributes to tumor progression, yet the underlying regulatory mechanisms remain poorly understood. In this study, we identify a transcriptional repression mechanism involving Preferentially Expressed Antigen in Melanoma (PRAME) and the transcription factor ETS2 as key modulators of ciliogenesis. We demonstrate an inverse correlation between PRAME expression and primary cilia formation in melanoma cells (R = -0.83, p = 0.042), and show that PRAME knockdown significantly promotes ciliogenesis, underscoring its role as a negative regulator. Integrative analyses combining our RNA-seq data with publicly available ChIP-seq data (GSE26439) and promoter motif analysis revealed that both PRAME and ETS2 are recruited to shared promoter regions of intraflagellar transport (IFT) genes, which are essential for cilia assembly. Notably, PRAME specifically interacts with ETS2, but not ETS1, indicating a selective and functionally relevant interaction. Similar to PRAME, ETS2 overexpression suppresses ciliogenesis and downregulates IFT gene expression. Mechanistically, the PRAME-ETS2 complex recruits histone deacetylase 1 (HDAC1) to IFT gene promoters, leading to epigenetic silencing via histone deacetylation. Together, these findings suggest that PRAME and ETS2 cooperatively suppress ciliogenesis in melanoma cells, proposing a previously unrecognized epigenetic mechanism of ciliary loss. This mechanism broadens our understanding of melanoma progression and highlights the role of the PRAME-ETS2-HDAC1 axis in regulating ciliogenesis.