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

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2760-2765
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
Publication statusPublished - 2012 Feb 21
Externally publishedYes

ASJC Scopus subject areas

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    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