Document Detail

Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin.
MedLine Citation:
PMID:  23041974     Owner:  NLM     Status:  MEDLINE    
Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.
Lihua Min; Yuan Ji; Latifa Bakiri; Zhixin Qiu; Jin Cen; Xiaotao Chen; Lingli Chen; Harald Scheuch; Hai Zheng; Lunxiu Qin; Kurt Zatloukal; Lijian Hui; Erwin F Wagner
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-07
Journal Detail:
Title:  Nature cell biology     Volume:  14     ISSN:  1476-4679     ISO Abbreviation:  Nat. Cell Biol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-07     Completed Date:  2013-01-16     Revised Date:  2013-05-13    
Medline Journal Info:
Nlm Unique ID:  100890575     Medline TA:  Nat Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1203-11     Citation Subset:  IM    
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Yueyang Road 320, Shanghai 200031, China.
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MeSH Terms
Blotting, Western
Chromatin Immunoprecipitation
Inhibitor of Apoptosis Proteins / genetics,  metabolism*
Liver Neoplasms / genetics,  metabolism*
Protein Binding
Real-Time Polymerase Chain Reaction
Signal Transduction / genetics,  physiology
Sirtuins / genetics,  metabolism*
Transcription Factor AP-1 / genetics,  metabolism*
Reg. No./Substance:
0/BIRC5 protein, human; 0/Inhibitor of Apoptosis Proteins; 0/Transcription Factor AP-1; EC protein, mouse; EC 3.5.1.-/SIRT6 protein, human; EC 3.5.1.-/Sirtuins
Erratum In:
Nat Cell Biol. 2013 Apr;15(4):440

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