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Nature Research, Nature Cell Biology, 4(15), p. 440-440

DOI: 10.1038/ncb2726

Nature Research, Nature Cell Biology, 11(14), p. 1203-1211

DOI: 10.1038/ncb2590

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Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.