@article{1c46e841c00f45fd8688d77168bc8f14,
title = "PAF remodels the DREAM complex to bypass cell quiescence and promote lung tumorigenesis",
abstract = "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.",
keywords = "Cell Cycle, DREAM complex, KIAA0101, KRAS, PAF, PCLAF, PCNA, RBBP4, cell quiescence, lung cancer",
author = "Kim, {Moon Jong} and Christopher Cervantes and Jung, {Youn Sang} and Xiaoshan Zhang and Jie Zhang and Lee, {Sung Ho} and Sohee Jun and Larisa Litovchick and Wenqi Wang and Junjie Chen and Bingliang Fang and Park, {Jae Il}",
note = "Funding Information: We are grateful to Kwon-Sik Park, Hee Kee Kim, Pierre D. McCrea, and Amy Ninetto for constructive comments on the manuscript. We thank Sabrina L. Spencer for providing the DHB-Venus reporter and Min Gyu Lee for providing the lung cancer cell lines. We also thank Esther M. Lien, Brittney Lozzi, and Tianyu Wang for technical support. This work was supported by grants from the Cancer Prevention and Research Institute of Texas ( RP140563 and RP200315 to J.-I.P.), the National Institutes of Health ( 2R01 CA193297 to J.-I.P.), the U.S. Department of Defense Peer Reviewed Cancer Research Program ( CA140572 to J.-I.P.), an Institutional Research Grant (MD Anderson Cancer Center to J.-I.P.), a Specialized Program of Research Excellence (SPORE) grant in endometrial cancer from the National Cancer Institute ( P50 CA83639 to J.-I.P.), and Radiation Oncology Research Initiatives (MD Anderson Cancer Center to M.J.K.) . PDX generation and annotation were supported by The University of Texas MD Anderson Cancer Center{\textquoteright}s Moon Shots Program, SPORE grant ( CA070907 ), and The University of Texas PDX Development and Trial Center grant ( U54CA224065 ). The core facilities used (DNA sequencing, Genetically Engineered Mouse Facility, and Small Animal Imaging Facility) are supported by Cancer Center Support Grant P30 CA016672 from the National Cancer Institute to MD Anderson Cancer Center. Publisher Copyright: {\textcopyright} 2021 The University of Texas MD Anderson Cancer Center",
year = "2021",
month = apr,
day = "15",
doi = "10.1016/j.molcel.2021.02.001",
language = "English (US)",
volume = "81",
pages = "1698--1714.e6",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "8",
}