Abstract
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.
Highlights
Glioblastoma (GBM) is the most malignant primary brain tumor in adults with a dismal prognosis of only 15 to 18 months [1]
The clones expressing the mutant USP15C298S formed more and bigger colonies in soft agar than the EGFP-vector controls (Figure 1). This observation may suggest that the Ubiquitin Specific Peptidase 15 (USP15) mutant USP15C298S out-competes the endogenous USP15 leading to enhanced cell proliferation in LN-229 and LN428 in vitro
Our previous analyses of GBM datasets have pointed to the de-ubiquitinase USP15 as a candidate tumor suppressor gene for GBM based on gene expression and gene CNV patterns [4]
Summary
Glioblastoma (GBM) is the most malignant primary brain tumor in adults with a dismal prognosis of only 15 to 18 months [1]. In a screen of a cohort of GBM for aberrantly expressed genes to infer underlying molecular alterations, we identified Ubiquitin Specific Peptidase 15 (USP15) (12q14.1) to be associated with genomic deletions, suggestive of a potential tumor suppressing function in GBM [4]. The region 12q14-15, comprising the USP15 locus, has been identified as a breakpoint rich region (BER) affecting a subset of GBM. BER results in complex patterns of gene alterations, including deletions, amplifications, rearrangements, and fusions that have been associated with worse outcome [5]. This chromosomal region is flanked by the proto-oncogenes CDK4 and MDM2 that are amplified individually or together in a subset of GBM, and coamplification overlaps significantly with BER
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
