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

被引：41

作者：

Kim, Moon Jong ^{[1
]}

Cervantes, Christopher ^{[1
]}

Jung, Youn-Sang ^{[1
,8
]}

Zhang, Xiaoshan ^{[2
]}

Zhang, Jie ^{[1
]}

Lee, Sung Ho ^{[1
]}

Jun, Sohee ^{[1
]}

Litovchick, Larisa ^{[3
,4
]}

Wang, Wenqi ^{[5
]}

Chen, Junjie ^{[1
]}

Fang, Bingliang ^{[2
]}

Park, Jae-Il ^{[1
,6
,7
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA

[3] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA

[4] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA

[5] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA

[6] Univ Texas MD Anderson UTHlth Grad Sch Biomed Sci, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Program Genet & Epigenet, Houston, TX 77030 USA

[8] Chung Ang Univ, Dept Life Sci, Seoul 06974, South Korea

来源：

MOLECULAR CELL | 2021年 / 81卷 / 08期

基金：

美国国家卫生研究院;

关键词：

M1 TRANSCRIPTION FACTOR; HEPATOCELLULAR-CARCINOMA; NUCLEAR ANTIGEN; EARLY-STAGE; CYCLIN B1; CANCER; EXPRESSION; KIAA0101; PROTEIN; OVEREXPRESSION;

D O I：

10.1016/j.molcel.2021.02.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1698 / +

页数：23

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