p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

被引:326
作者
Moon, Sung-Hwan [1 ]
Huang, Chun-Hao [2 ,3 ,4 ]
Houlihan, Shauna L. [2 ]
Regunath, Kausik [1 ]
Freed-Pastor, William A. [1 ,8 ]
Morris, John P. [2 ]
Tschaharganeh, Darjus F. [2 ,9 ,10 ]
Kastenhuber, Edward R. [2 ,5 ]
Barsotti, Anthony M. [1 ,11 ]
Culp-Hill, Rachel [6 ]
Xue, Wen [12 ]
Ho, Yu-Jui [2 ]
Baslan, Timour [2 ]
Li, Xiang [2 ,3 ]
Mayle, Allison [2 ]
de Stanchina, Elisa [2 ]
Zender, Lars [4 ]
Tong, David R. [1 ]
D'Alessandro, Angelo [6 ]
Lowe, Scott W. [2 ,7 ]
Prives, Carol [1 ]
机构
[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA
[2] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10065 USA
[3] Cornell Univ, Weill Grad Sch Med Sci, Cell & Dev Biol Program, New York, NY 10065 USA
[4] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA
[5] Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY 10065 USA
[6] Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Aurora, CO 80045 USA
[7] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA
[8] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
[9] German Canc Res Ctr, Helmholtz Grp Cell Plast & Epigenet Remodeling, Neuenheimer Feld 224, D-69120 Heidelberg, Germany
[10] Univ Hosp, Inst Pathol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany
[11] VL47 Inc, New York, NY 10016 USA
[12] Univ Massachusetts, Med Sch, Worcester, MA 01605 USA
基金
美国国家科学基金会;
关键词
STATIN USE; HEPATOCELLULAR-CARCINOMA; CANCER SURVIVAL; BREAST-CANCER; TARGET GENE; TGF-BETA; CHOLESTEROL; ABCA1; RISK; TRANSPORT;
D O I
10.1016/j.cell.2018.11.011
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
There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.
引用
收藏
页码:564 / +
页数:36
相关论文
共 70 条
[1]   Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs [J].
Adams, CM ;
Reitz, J ;
De Brabander, JK ;
Feramisco, JD ;
Li, L ;
Brown, MS ;
Goldstein, JL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (50) :52772-52780
[2]   The current evidence on statin use and prostate cancer prevention: are we there yet? [J].
Alfaqih, Mahmoud A. ;
Allott, Emma H. ;
Hamilton, Robert J. ;
Freeman, Michael R. ;
Freedland, Stephen J. .
NATURE REVIEWS UROLOGY, 2017, 14 (02) :107-119
[3]   Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms [J].
Allen, Mary Ann ;
Andrysik, Zdenek ;
Dengler, Veronica L. ;
Mellert, Hestia S. ;
Guarnieri, Anna ;
Freeman, Justin A. ;
Sullivan, Kelly D. ;
Galbraith, Matthew D. ;
Luo, Xin ;
Kraus, W. Lee ;
Dowell, Robin D. ;
Espinosa, Joaquin M. .
ELIFE, 2014, 3
[4]   The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].
Barretina, Jordi ;
Caponigro, Giordano ;
Stransky, Nicolas ;
Venkatesan, Kavitha ;
Margolin, Adam A. ;
Kim, Sungjoon ;
Wilson, Christopher J. ;
Lehar, Joseph ;
Kryukov, Gregory V. ;
Sonkin, Dmitriy ;
Reddy, Anupama ;
Liu, Manway ;
Murray, Lauren ;
Berger, Michael F. ;
Monahan, John E. ;
Morais, Paula ;
Meltzer, Jodi ;
Korejwa, Adam ;
Jane-Valbuena, Judit ;
Mapa, Felipa A. ;
Thibault, Joseph ;
Bric-Furlong, Eva ;
Raman, Pichai ;
Shipway, Aaron ;
Engels, Ingo H. ;
Cheng, Jill ;
Yu, Guoying K. ;
Yu, Jianjun ;
Aspesi, Peter, Jr. ;
de Silva, Melanie ;
Jagtap, Kalpana ;
Jones, Michael D. ;
Wang, Li ;
Hatton, Charles ;
Palescandolo, Emanuele ;
Gupta, Supriya ;
Mahan, Scott ;
Sougnez, Carrie ;
Onofrio, Robert C. ;
Liefeld, Ted ;
MacConaill, Laura ;
Winckler, Wendy ;
Reich, Michael ;
Li, Nanxin ;
Mesirov, Jill P. ;
Gabriel, Stacey B. ;
Getz, Gad ;
Ardlie, Kristin ;
Chan, Vivien ;
Myer, Vic E. .
NATURE, 2012, 483 (7391) :603-607
[5]   Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma [J].
Bellomo, Claudia ;
Caja, Laia ;
Fabregat, Isabel ;
Mikulits, Wolfgang ;
Kardassis, Dimitris ;
Heldin, Carl-Henrik ;
Moustakas, Aristidis .
CELL DEATH AND DIFFERENTIATION, 2018, 25 (05) :885-903
[6]   Trimmomatic: a flexible trimmer for Illumina sequence data [J].
Bolger, Anthony M. ;
Lohse, Marc ;
Usadel, Bjoern .
BIOINFORMATICS, 2014, 30 (15) :2114-2120
[7]   The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J].
Brown, MS ;
Goldstein, JL .
CELL, 1997, 89 (03) :331-340
[8]   Requirement for p53 and p21 to sustain G2 arrest after DNA damage [J].
Bunz, F ;
Dutriaux, A ;
Lengauer, C ;
Waldman, T ;
Zhou, S ;
Brown, JP ;
Sedivy, JM ;
Kinzler, KW ;
Vogelstein, B .
SCIENCE, 1998, 282 (5393) :1497-1501
[9]   Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study [J].
Cardwell, Chris R. ;
Mc Menamin, Una ;
Hughes, Carmel M. ;
Murray, Liam J. .
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2015, 24 (05) :833-841
[10]   Statin and aspirin for prevention of hepatocellular carcinoma: What are the levels of evidence? [J].
Carrat, Fabrice .
CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY, 2014, 38 (01) :9-11