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

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.

Clinicopathological and prognostic significance of ubiquitin‐specific peptidase 15 and its relationship with transforming growth factor‐β receptors in patients with pancreatic ductal adenocarcinoma

“…Similarly, Xu et al also demonstrated that USP15 promoted tumor cell invasion and proliferation in glioblastoma 20 . Nevertheless, Oikonomaki et al reported that USP15 suppressed glioblastoma cell growth by attenuating WNT pathway activity, 21 indicating a latent dual role of USP15 as both an oncogene and tumor‐suppressor gene. In addition, USP15 gene amplification was observed in breast and ovarian cancers, indicating that the oncogenic role of USP15 might be prevalent in malignancies 16 .…”

AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis

“…S2A–B). To clarify the mechanism underlying AR ubiquitination, the interaction of AR with 6 tumor-suppressive E3 ligases [[22], [23], [24], [25], [26], [27]] including FBXL2, HECTD1, VHL, TRIM13, FBXW7 and SMURF2 were determined. Of that, the AR-FBXL2 interaction was detected after ALZ003 treatment (Fig.…”

Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway

“…We identified HECTD1 as LXN associating protein. Because HECTD1 is an E3 ubiquitin ligase, which widely involved in the regulation of cancer invasion 37,38 , this prompted us to hypothesis that HECTD1 may be related to the ubiquitylation of IκBα. Interestingly, HECTD1 may interact with adenomatous polyposis coli (APC), whose dysfunction has been linked to the development of most forms of colorectal cancer 39 .…”