Research Papers:

Ubiquitin Specific Peptidase 15 (USP15) suppresses glioblastoma cell growth via stabilization of HECTD1 E3 ligase attenuating WNT pathway activity

Maria Oikonomaki, Pierre Bady and Monika E. Hegi _

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Oncotarget. 2017; 8:110490-110502. https://doi.org/10.18632/oncotarget.22798

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Maria Oikonomaki1, Pierre Bady1,2,3 and Monika E. Hegi1

1Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland

2Department of Research and Education, University Hospital Lausanne, Lausanne, Switzerland

3Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

Correspondence to:

Monika E. Hegi, email: Monika.Hegi@CHUV.ch

Keywords: glioblastoma; USP15; HECTD1; tumor suppressor; WNT pathway

Received: September 12, 2017     Accepted: November 13, 2017     Published: November 30, 2017


Expression based prediction of new genomic alterations in glioblastoma identified the de-ubiquitinase Ubiquitin Specific Peptidase 15 (USP15) as potential tumor suppressor gene associated with genomic deletions (11%). Ectopic expression of USP15 in glioblastoma cell-lines reduced colony formation and growth in soft agar, while overexpression of its functional mutant had the opposite effect. Evaluation of the protein binding network of USP15 by Mass Spectrometry in glioblastoma cells uncovered eight novel interacting proteins, including HECT Domain Containing E3 Ubiquitin Protein Ligase 1 (HECTD1), whose mouse homologue has been associated with an inhibitory effect on the WNT-pathway. USP15 de-ubiquitinated and thereby stabilized HECTD1 in glioblastoma cells, while depletion of USP15 led to decreased HECTD1 protein levels. Expression of USP15 in glioblastoma cells attenuated WNT-pathway activity, while expression of the functional mutant enhanced the activity. Modulation of HECTD1 expression pheno-copied the effects observed for USP15. In accordance, human glioblastoma display a weak but significant negative correlation between USP15 and AXIN2 expression. Taken together, the data provide evidence that USP15 attenuates the canonical WNT pathway mediated by stabilization of HECTD1, supporting a tumor suppressing role of USP15 in a subset of glioblastoma.

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