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Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression

Abstract

LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-κB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.

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Acknowledgements

Funding for this study was provided by Cancer Research UK (DEN, HCW, IGM) and the Medical Research Council (HJT). We thank Jonathon D Licht for the PLZF reporter construct 4xIL-3R-tkLUC, Zhou Wang (Chicago) for PLZF expression construct, Krishna Chatterjee (Cambridge) for pEF-BOS-β-gal construct. We also thank Wendy Bickmore for LYRIC/AEG-1 antibodies (Edinburgh) and Maria Carmo-Fonseca (Lisbon) for the anti-coilin antibody. We are very grateful to Antonio Ramos-Montoya (Cambridge) for help and advice with ChIP and qRT–PCR. We acknowledge the support of the Cancer Research UK Cambridge Genomics Core Facility and Microscopy Core Facility, The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.

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Correspondence to H C Whitaker.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Thirkettle, H., Mills, I., Whitaker, H. et al. Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression. Oncogene 28, 3663–3670 (2009). https://doi.org/10.1038/onc.2009.223

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