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The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein

Oncogene volume 32, pages 3819–3828 (2013)Cite this article

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A Corrigendum to this article was published on 01 October 2015

Abstract

The promyelocytic leukemia (PML) protein is a tumor suppressor originally identified in acute promyelocytic leukemia and implicated in tumorigenesis in multiple forms of cancer. Here, we demonstrate that the PML protein undergoes ubiquitination-mediated degradation facilitated by an E3 ligase UHRF1 (ubiquitin-like with PHD and RING finger domains 1), which is commonly upregulated in various human malignancies. Furthermore, UHRF1 negatively regulates PML protein accumulation in primary human umbilical vein endothelial cells (HUVECs), HEK 293 cells and cancer cells. Knockdown of UHRF1 upregulates whereas ectopic overexpression of UHRF1 downregulates protein abundance of endogenous or exogenous PML, doing so through its binding to the N-terminus of PML. Overexpression of wild-type UHRF1 shortens PML protein half-life and promotes PML polyubiquitination, whereas deletion of the RING domain or coexpression of the dominant-negative E2 ubiquitin-conjugating enzyme, E2D2, attenuates this modification to PML. Finally, knockdown of UHRF1 prolongs PML half-life and increases PML protein accumulation, yet inhibits cell migration and in vitro capillary tube formation, whereas co-knockdown of PML compromises this inhibitory effect. These findings suggest that UHRF1 promotes the turnover of PML protein, and thus targeting UHRF1 to restore PML-mediated tumor suppression represents a promising, novel, anticancer strategy.

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Acknowledgements

We thank Dr David Samols for his comments on the manuscript. D Factor is supported by training Grant T32HD07104. This project is supported by the NIH through R01 DK078965, HL093269 and Case Comprehensive Cancer Center Program in Aging and Energy Balance, NCI P20 CA103767 to H-Y Kao and CA127590 to Z Wang.

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Authors and Affiliations

  1. Department of Biochemistry and Case Western Reserve University, Cleveland, OH, USA

    D Guan, D Factor, Yu Liu & H-Y Kao

  2. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Z Wang

  3. The Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA

    Z Wang & H-Y Kao

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  2. D Factor
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Correspondence to H-Y Kao.

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Guan, D., Factor, D., Liu, Y. et al. The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein. Oncogene 32, 3819–3828 (2013). https://doi.org/10.1038/onc.2012.406

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