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TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas

Oncogene volume 36, pages 3740–3748 (2017)Cite this article

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Abstract

TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science (JSPS) and by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. Zhuoran Liu was supported by a fellowship from the China Scholarship Council.

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Authors and Affiliations

  1. Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Z Liu, K Yanagisawa, S Griesing, M Iwai, K Kano, N Hotta, T Kajino, M Suzuki & T Takahashi

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  1. Z Liu
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Correspondence to T Takahashi.

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Liu, Z., Yanagisawa, K., Griesing, S. et al. TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. Oncogene 36, 3740–3748 (2017). https://doi.org/10.1038/onc.2016.524

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