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

Chiba, Naokazu; Comaills, Valentine; Shiotani, Bunsyo; Takahashi, Fumiyuki; Shimada, Takuya; Tajima, Ken; Winokur, Daniel; Hayashida, Tetsu; Willers, Henning; Brachtel, Elena F.; Vivanco, María dM; Haber, Daniel A.; Zou, Lee; Maheswaran, Shyamala

doi:10.1073/pnas.1018867108

Cited by 84 publications

(59 citation statements)

References 27 publications

(29 reference statements)

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“…This appears to be the case in breast cancer cell lines, in which it was shown that HOXB9 induces both EMT and confers resistance to ionizing radiation by accelerating the DNA damage response (43). In another report, it was shown that ATMmediated Snail serine 100 phosphorylation regulates cellular radiosensitivity (44).…”

Section: Discussionmentioning

confidence: 94%

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Jong

Hoeve

Grénman

et al. 2015

Clinical Cancer Research

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Purpose: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells, and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biologic processes that could be targeted to overcome intrinsic resistance.Experimental Design: We analyzed both microRNA and mRNA expression in a large panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of patients with laryngeal cancer.Results: miRs, mRNAs, and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial-to-mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of patients with laryngeal cancer.Conclusions: These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pretreatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors.

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Section: Discussionmentioning

confidence: 94%

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Jong

Hoeve

Grénman

et al. 2015

Clinical Cancer Research

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“…HOXB9 was reported to be frequently overexpressed in invasive human breast cancer, and promotes epithelial to mesenchymal transition (EMT) (6,11,12). Moreover, upregulation of HOXB9 in lung adenocarcinoma patients predicts poor outcomes (13).…”

Section: Introductionmentioning

confidence: 99%

PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6

Wan

Zhan

et al. 2016

Nucleic Acids Res

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HOXB9 is a homeobox domain-containing transcription factor, playing an important role in embryonic development and cancer progression. However, the precise post-translational modifications (PTMs) of HOXB9 and the corresponding roles are unclear. Here, we report that acetyltransferase p300/CBP-associated factor (PCAF) interacts with and acetylates HOXB9 both in vivo and in vitro. Conversely, the acetylation of HOXB9 can be reversed by deacetylase SIRT1. Furthermore, we found that HOXB9 is acetylated at lysine 27 (AcK27). Functionally, in contrast to the wild type HOXB9, AcK27-HOXB9 decreased its capacity in promoting lung cancer cell migration and tumor growth in mice. Mechanistically, AcK27-HOXB9 suppresses the transcription of its target gene Jumonji domain-containing protein 6 (JMJD6) by direct occupying the promoter of JMJD6 gene. For clinical relevance, elevated HOXB9 acetylation at K27 predicts a better prognosis in lung adenocarcinoma patients. Taken together, we identified the first PTM of HOXB9 by demonstrating that HOXB9 can be acetylated and AcK27-HOXB9 counteracts the role of the wild-type HOXB9 in regulating lung adenocarcinoma progression.

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“…Kanamoto and colleagues reported that TGFb1 was involved in DNA repair mechanisms by modulating Rad51 expression in Mv1Lu epithelial cells (24). Chiba and colleagues recently reported that TGFb accelerated the DNA damage response and subsequently conferred radioresistance (25). Marx also suggested a DNA repair defect associated with mutations in a TGFb receptor (26).…”

Section: Discussionmentioning

confidence: 99%

TGFβ1 Protects Cells from γ-IR by Enhancing the Activity of the NHEJ Repair Pathway

Kim

Lee

et al. 2015

Molecular Cancer Research

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Several groups have reported that TGFb1 regulates cellular responses to g-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFb1 in cellular responses to g-irradiation was investigated in detail. The data indicate that TGFb1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFb1 was examined. Studies reveal that TGFb1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFb1-induced protection against IR. Overall, these data indicate that TGFb1 facilitates the NHEJ repair process upon g-irradiation and thereby enhances long-term survival.Implications: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFb signaling pathway. Mol Cancer Res; 13(2); 319-29. Ó2014 AACR.

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

Cited by 84 publications

References 27 publications

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6

TGFβ1 Protects Cells from γ-IR by Enhancing the Activity of the NHEJ Repair Pathway

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