期刊
MOLECULAR CELL
卷 81, 期 8, 页码 1698-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2021.02.001
关键词
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资金
- Cancer Prevention and Research Institute of Texas [RP140563, RP200315]
- National Institutes of Health [2R01 CA193297]
- U.S. Department of Defense Peer Reviewed Cancer Research Program [CA140572]
- Institutional Research Grant (MD Anderson Cancer Center)
- Specialized Program of Research Excellence (SPORE) grant in endometrial cancer from the National Cancer Institute [P50 CA83639]
- Radiation Oncology Research Initiatives (MD Anderson Cancer Center)
- University of Texas MD Anderson Cancer Center's Moon Shots Program, SPORE grant [CA070907]
- Cancer Center Support Grant from the National Cancer Institute [P30 CA016672]
- University of Texas PDX Development and Trial Center grant [U54CA224065]
PAF drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex. Its depletion induces cell quiescence in lung adenocarcinoma cells and inhibits tumor growth, suggesting the PAF-DREAM axis as a potential therapeutic target in lung cancer.
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 DREAMtarget 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.
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