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HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

Oncogene volume 30, pages 3024–3035 (2011)Cite this article

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Abstract

DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxia-telangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage- and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.

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Acknowledgements

We thank V Costanzo for revision of the paper and I Pellegrino for technical support. We are grateful to MB Kastan for providing the pFLAG-ATM expression construct and to D Ginsberg for the pLuc-ATM reporter vector. This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC). DP is recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

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Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli “Federico II”, Naples, Italy

    D Palmieri, T Valentino, D D'Angelo, I De Martino, I Postiglione, M Fedele & A Fusco

  2. Istituto di Biostrutture e Bioimmagini del CNR, Naples, Italy

    R Pacelli

  3. Department of Molecular Virology, Division of Human Cancer Genetics, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    D Palmieri & C M Croce

  4. NOGEC (Naples Oncogenomic Center)-CEINGE, Biotecnologie Avanzate, via Comunale Margherita, Naples, Italy

    A Fusco

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  1. D Palmieri
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  2. T Valentino
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  3. D D'Angelo
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  4. I De Martino
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  6. R Pacelli
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  7. C M Croce
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  8. M Fedele
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  9. A Fusco
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Correspondence to A Fusco.

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Palmieri, D., Valentino, T., D'Angelo, D. et al. HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents. Oncogene 30, 3024–3035 (2011). https://doi.org/10.1038/onc.2011.21

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