Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin
| Autor: | Latifa Bakiri, Kurt Zatloukal, Xiaotao Chen, Erwin F. Wagner, Zhixin Qiu, Lijian Hui, Harald Scheuch, Lun-Xiu Qin, Yuan Ji, Lihua Min, Hai Zheng, Lingli Chen, Jin Cen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
SIRT6 Chromatin Immunoprecipitation Survivin Blotting Western In Vitro Techniques Real-Time Polymerase Chain Reaction medicine.disease_cause Inhibitor of Apoptosis Proteins Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Sirtuins 030304 developmental biology 0303 health sciences biology Liver Neoplasms Cell Biology medicine.disease Immunohistochemistry Cell biology 3. Good health Transcription Factor AP-1 Histone 030220 oncology & carcinogenesis Cancer cell biology.protein Signal transduction Carcinogenesis Liver cancer Chromatin immunoprecipitation Protein Binding Signal Transduction |
| Zdroj: | Nature Cell Biology |
| ISSN: | 1465-7392 |
| DOI: | 10.1038/ncb2726 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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