Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses

Naokazu Chiba, Valentine Comaills, Bunsyo Shiotani, Fumiyuki Takahashi, Toshiyuki Shimada, Ken Tajima, Daniel Winokur, Tetsu Hayashida, Henning Willers, Elena Brachtel, Maria D.M. Vivanco, Daniel A. Haber, Lee Zou, Shyamala Maheswaran

研究成果: Article

59 引用 (Scopus)

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Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the doublestranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-β, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9-TGF-β-ATM axis on checkpoint activation and DNA repair, suggesting that TGF-β may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9- overexpressing breast tumors.

元の言語English
ページ(範囲)2760-2765
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
109
発行部数8
DOI
出版物ステータスPublished - 2012 2 21
外部発表Yes

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ASJC Scopus subject areas

  • General

これを引用

Chiba, N., Comaills, V., Shiotani, B., Takahashi, F., Shimada, T., Tajima, K., Winokur, D., Hayashida, T., Willers, H., Brachtel, E., Vivanco, M. D. M., Haber, D. A., Zou, L., & Maheswaran, S. (2012). Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses. Proceedings of the National Academy of Sciences of the United States of America, 109(8), 2760-2765. https://doi.org/10.1073/pnas.1018867108