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15-LOX-1 transcription suppression through the NuRD complex in colon cancer cells

Oncogene volume 28, pages 1496–1505 (2009)Cite this article

Abstract

15-Lipoxygenase-1 (15-LOX-1) is transcriptionally silenced in cancer cells, and its transcription reactivation (for example, through histone deacetylase inhibitors (HDACIs)) restores apoptosis to cancer cells. However, the exact mechanism underlying 15-LOX-1 transcription reactivation in cancer cells is still undefined. Therefore, we evaluated the critical mechanisms required for 15-LOX-1 transcription reactivation in colon cancer cells. Specific HDAC1 and HDAC2 inhibition activated 15-LOX-1 transcription. 15-LOX-1 transcription was repressed through transcription repressor complex recruitment in the region of −120 to −391 of the 15-LOX-1 promoter. The nucleosome remodeling and histone deacetylase (NuRD) repression complex was recruited to this region. Depsipeptide significantly reduced the recruitment of NuRD key components (for example, metastasis-associated protein 1 (MTA1) and HDAC1) to the 15-LOX-1 promoter before 15-LOX-1 transcriptional activation. Knock down of NuRD key components (for example, MTA1 and HDAC1) by small interfering RNA (siRNA) activated 15-LOX-1 transcription, as measured by luciferase reporter assays in stably transfected SW480 cells with the 15-LOX-1 promoter construct of the −391, but not the −120 region. Relative to expression in normal tissue, MTA1 expression in colorectal cancer mucosa from colorectal cancer patients was negatively related to 15-LOX-1 expression. Thus, our results show that NuRD contributes to 15-LOX-1 transcription suppression in colon cancer cells and that HDACIs can inhibit NuRD recruitment to a promoter to activate gene transcription, as in the case of 15-LOX-1.

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Acknowledgements

This study was supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services R01 grants CA106577 and CA104278; the Caroline Wiess Law Endowment for Cancer Prevention; the Jerry and Maury Rubenstein Foundation and the National Colorectal Cancer Research Alliance. We thank Merck and Company Inc., Gloucester Pharmaceuticals and the National Cancer Institute for providing SAHA and depsipeptide. We also thank Ann M. Sutton, Department of Scientific Publications, the University of Texas M D Anderson Cancer Center, for editing the manuscript.

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Authors and Affiliations

  1. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Zuo & I Shureiqi

  2. Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J S Morris

  3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R Broaddus

  4. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    I Shureiqi

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Correspondence to I Shureiqi.

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Zuo, X., Morris, J., Broaddus, R. et al. 15-LOX-1 transcription suppression through the NuRD complex in colon cancer cells. Oncogene 28, 1496–1505 (2009). https://doi.org/10.1038/onc.2008.494

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