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

Moon Jong Kim; Christopher Cervantes; Youn-Sang Jung; Xiaoshan Zhang; Jie Zhang; Sung Ho Lee; Sohee Jun; Larisa Litovchick; Wenqi Wang; Junjie Chen; Bingliang Fang; Jae-Il Park

doi:10.1016/j.molcel.2021.02.001

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

Mol Cell. 2021 Apr 15;81(8):1698-1714.e6. doi: 10.1016/j.molcel.2021.02.001. Epub 2021 Feb 23.

Authors

Affiliations

¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea.
³ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁵ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
⁶ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jaeil@mdanderson.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

A549 Cells
Adenocarcinoma of Lung / genetics
Adenocarcinoma of Lung / pathology
Animals
Carcinogenesis / genetics*
Carcinogenesis / pathology
Cell Division / genetics
Cell Line
Cell Line, Tumor
Cell Proliferation / genetics
DNA-Binding Proteins / genetics*
Female
Humans
Kv Channel-Interacting Proteins / genetics*
Lung / pathology*
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
NIH 3T3 Cells
Repressor Proteins / genetics*
Transcriptional Activation / genetics
Transcriptome / genetics

Substances

DNA-Binding Proteins
KCNIP3 protein, human
Kv Channel-Interacting Proteins
PCLAF protein, human
Repressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding