PAF remodels the DREAM complex to bypass cell quiescence and promote lung tumorigenesis

The DREAM complex orchestrates cell quiescence and the cell cycle. However, how the DREAM complex is deregulated in cancer remains elusive. Here, we report that PAF (PCLAF/KIAA0101) drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex. PAF is highly expressed in lung adenocarcinoma (LUAD) and is associated with poor prognosis. Importantly, Paf knockout markedly suppressed LUAD development in mouse models. PAF depletion induced LUAD cell quiescence and growth arrest. PAF is required for the global expression of cell-cycle genes controlled by the repressive DREAM complex. Mechanistically, PAF inhibits DREAM complex formation by binding to RBBP4, a core DREAM subunit, leading to transactivation of DREAM target genes. Furthermore, pharmacological mimicking of PAF-depleted transcriptomes inhibited LUAD tumor growth. Our results unveil how the PAF-remodeled DREAM complex bypasses cell quiescence to promote lung tumorigenesis and suggest that the PAF-DREAM axis may be a therapeutic vulnerability in lung cancer. [Display omitted] •Paf KO suppresses lung adenocarcinoma (LUAD) development•PAF depletion induces cell quiescence and growth arrest of LUAD cells•PAF drives the global expression of cell-cycle genes by remodeling the DREAM complex•Pharmacological mimicking of PAF-depleted transcriptomes inhibits LUAD growth Bypassing cell quiescence and cell-cycle arrest is a crucial step for tumorigenesis. Here, Kim et al. show that a PAF-remodeled DREAM complex induces the global expression of cell-cycle genes, thereby evading quiescence and promoting lung tumorigenesis.