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Aberrant BLM cytoplasmic expression associates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer

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Abstract

Background

Bloom syndrome is a rare and recessive disorder characterized by loss-of-function mutations of the BLM gene, which encodes a RecQ 3′–5′ DNA helicase. Despite its putative tumor suppressor function, the contribution of BLM to human sporadic colorectal cancer (CRC) remains poorly understood.

Methods

The transcriptional regulation mechanism underlying BLM and related DNA damage response regulation in independent CRC subsets and a panel of derived cell lines was investigated by bioinformatics analysis, the transcriptomic profile, a CpG island promoter methylation assay, Western blot, and an immunolocalization assay.

Results

In silico analysis of gene expression data sets revealed that BLM is overexpressed in poorly differentiated CRC and exhibits a close connection with shorter relapse-free survival even after adjustment for prognostic factors and pathways that respond to DNA damage response through ataxia telangiectasia mutated (ATM) signaling. Functional characterization demonstrated that CpG island promoter hypomethylation increases BLM expression and associates with cytoplasmic BLM mislocalization and increased DNA damage response both in clinical CRC samples and in derived cancer cell lines. The DNA-damaging agent S-adenosylmethionine suppresses BLM expression, leading to the inhibition of cell growth following accumulation of DNA damage. In tumor specimens, cytoplasmic accumulation of BLM correlates with DNA damage and γH2AX and phosphorylated ATM foci and predicts long-term progression-free survival in metastatic patients treated with irinotecan.

Conclusions

Taken together, the findings of this study provide the first evidence that cancer-linked DNA hypomethylation and cytosolic BLM mislocalization might reflect compromised levels of DNA-repair activity and enhanced hypersensitivity to DNA-damaging agents in CRC patients.

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Acknowledgments

Part of this study was funded by the Italian Ministry of University and Research (MiUR) through a grant to Massimo Pancione. We would like to thank all the scientists who have contributed through their valuable advice to  this article's production.

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Authors and Affiliations

  1. Department of Sciences and Technologies, University of Sannio, Via Port’Arsa, 11, 82100, Benevento, Italy

    Carolina Votino & Massimo Pancione

  2. Department of Experimental and Clinical Medicine “Gaetano Salvatore”, University “Magna Grecia”, 88100, Catanzaro, Italy

    Carmelo Laudanna

  3. Department of Surgery and Oncology, University of Verona, 37129, Verona, Italy

    Pietro Parcesepe

  4. Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy

    Guido Giordano & Erminia Manfrin

  5. Department of Pathology, “Mater Salutis” Hospital, 37045, Legnago, VR, Italy

    Andrea Remo

  6. Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, Madrid, Spain

    Massimo Pancione

Authors
  1. Carolina Votino
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  2. Carmelo Laudanna
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  3. Pietro Parcesepe
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  4. Guido Giordano
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  5. Andrea Remo
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  6. Erminia Manfrin
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  7. Massimo Pancione
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Corresponding author

Correspondence to Massimo Pancione.

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Conflict of interest

The authors declare that they have no conflict of interest.

Funding

Part of this study was funded by the FUR and the Italian Ministry of University and Research (MiUR) by grants to Massimo Pancione.

Additional information

C. Votino, C. Laudanna, and P. Parcesepe are joint first authors.

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Votino, C., Laudanna, C., Parcesepe, P. et al. Aberrant BLM cytoplasmic expression associates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer. J Gastroenterol 52, 327–340 (2017). https://doi.org/10.1007/s00535-016-1222-0

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  • DOI: https://doi.org/10.1007/s00535-016-1222-0

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