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A role for Ubc9 in tumorigenesis

Oncogene volume 24, pages 2677–2683 (2005)Cite this article

Abstract

The post-translational modifications ubiquitination and sumoylation have been implicated in regulating many critical cellular pathways. Like ubiquitination, sumoylation is a multistep process involving maturation, activation, conjugation and deconjugation. Ubc9 is a sole E2-conjugating enzyme essential for sumoylation. We have previously shown that alterations of Ubc9 expression affect tumor drug responsiveness. However, it is not clear whether there is any link between sumoylation and tumorigenesis, even though alterations of the ubiquitination pathway can lead to the development of cancer. In this study, we found that Ubc9 expression levels were elevated in ovarian tumors compared to the matched normal ovarian specimens, suggesting that Ubc9 may play a role in tumorigenesis. To test this, we overexpressed a dominant-negative mutant of Ubc9 (Ubc9-DN) and wild-type Ubc9 (Ubc9-WT) in the MCF-7 human breast tumor cells. Inoculating these cells as xenografts in mice revealed that tumors expressing Ubc9-WT grew better than the vector control, while tumors expressing Ubc9-DN exhibited reduced growth. This pattern was also seen in these cells when grown in culture. To better understand the mechanism behind this observation, we profiled gene expressions in these cells by microarray analysis and found alterations in expression of the pro-oncogene bcl-2 in these Ubc9-DN- and Ubc9-WT-expressing cells. Consistent with the bcl-2 results, subsequent studies revealed a higher rate of apoptosis and poor survival for the MCF-7 cells expressing Ubc9-DN, which are associated with downregulation of bcl-2. Together, these results suggest a role for Ubc9 in tumorigenesis at least partially through regulation of bcl-2 expression.

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Abbreviations

DN:

dominant negative

RT:

reverse transcription

PCR:

polymerase chain reaction

SUMO:

small ubiquitin-related modifier

Ub:

ubiquitin

WT:

wild type

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Acknowledgements

This work was supported by Grants CA40570, CA30103 (both to WTB) and CA102630 (to YM) from the National Institutes of Health, DAMD17-99-19220 (to WTB and YM) from DOD, and National Cancer Institute Grants CA27469 to the Gynecologic Oncology Group (GOG) with subcontracts for the GOG Molecular Pharmacology Core Laboratory and GOG Tissue Bank. We thank Martina Vaskova for her critical review of the manuscript.

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Authors and Affiliations

  1. Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Yin-Yuan Mo, Yanni Yu, P L Rachel Ee & William T Beck

  2. Department of Medicine, Section of Hematology-Oncology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Elena Theodosiou

  3. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60612, USA

    William T Beck

  4. Gynecologic Oncology Group Core Laboratory in Molecular Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    William T Beck

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  1. Yin-Yuan Mo
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Correspondence to Yin-Yuan Mo.

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Mo, YY., Yu, Y., Theodosiou, E. et al. A role for Ubc9 in tumorigenesis. Oncogene 24, 2677–2683 (2005). https://doi.org/10.1038/sj.onc.1208210

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