title: Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin.
abstract: 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.
authors.affiliation: 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.
authors.forename: Lihua
authors.initials: L
authors.lastname: Min
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Qiu
authors.forename: Jin
authors.initials: J
authors.lastname: Cen
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Chen
authors.forename: Lingli
authors.initials: L
authors.lastname: Chen
authors.forename: Harald
authors.initials: H
authors.lastname: Scheuch
authors.forename: Hai
authors.initials: H
authors.lastname: Zheng
authors.forename: Lunxiu
authors.initials: L
authors.lastname: Qin
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Lijian
authors.initials: L
authors.lastname: Hui
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D018808:Transcription Factor AP-1; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins