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HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins

Oncogene volume 26, pages 4825–4832 (2007)Cite this article

Abstract

Human enhancer of invasion, clone 10 (HEI10) (CCNB1IP1) was first described as a RING-finger family ubiquitin ligase that regulates cell cycle by interacting with cyclin B and promoting its degradation. Subsequently, other studies suggested specific upregulation of HEI10 in metastatic melanoma and demonstrated direct interaction between HEI10 and the tumor suppressor Merlin, encoded by the neurofibromatosis 2 gene. These and other results led us to hypothesize that HEI10 also influences the processes of cell migration and metastasis. We here show that cells with depleted HEI10 both migrate more rapidly and invade more effectively than control cells. HEI10 depletion post-transcriptionally increases the expression of a group of promotility regulatory proteins including p130Cas, paxillin, Cdk1 and cyclin B2, but excluding Merlin. Among these, only inhibition of Cdk1/cyclin B activity specifically reversed the motility and invasion of HEI10-depleted cells. Finally, HEI10 is abundantly transcribed in many human tissues, and particularly abundant in some tumor cell lines, suggesting that it may be commonly involved in coordinating cell cycle with cell migration and invasion.

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Acknowledgements

We thank Margret Einarson, Cynthia Spittle, Meenhard Herlyn and Hong Wu for help with the collection and preparation of cell lines for RNA analysis. We also thank Ilya Serebriiskii for help with some experiments. We greatly appreciate the efforts of Dr Brian Egleston in the statistical analysis of data. We thank Dr Tony Yeung, director of the FCCC Biochemistry and Biotechnology facility for Real-Time PCR and DNA synthesis services This work and the authors were supported by NIH RO1 CA63366 and by Translational Pilot Project funding from the Tobacco Settlement from the State of Pennsylvania, Department of Health (to EAG) and by an Appropriation from the Commonwealth of Pennsylvania, by NIH core Grant CA-06927 and support from the Pew Charitable Fund (to Fox Chase Cancer Center). DD was a recipient of the Plain and Fancy Fellowship of the Fox Chase Cancer Center Board of Associates.

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  1. D Dadke

    Present address: 2Current address: Stem Cell Research Center, Manipal Hospital, Bangalore, India.,

Authors and Affiliations

  1. Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA

    M K Singh, E Nicolas, W Gherraby, D Dadke, S Lessin & E A Golemis

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  1. M K Singh
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Correspondence to E A Golemis.

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

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Singh, M., Nicolas, E., Gherraby, W. et al. HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins. Oncogene 26, 4825–4832 (2007). https://doi.org/10.1038/sj.onc.1210282

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