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

• DOI: 10.1073/pnas.1018867108
• Publication Date: 2011-09-20T08:23:28Z
• Authors: 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
• Keywords: Radioresistance; FANCD2

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