USP36 Promotes Tumorigenesis and Drug Sensitivity of Glioblastoma by Deubiquitinating and Stabilizing ALKBH5

Authors

Guoqiang Chang
Gloria S Xie
Li Ma
Peng Li
Linlin Li
Hope T Richard

Publication Date

5-4-2023

Journal

Neuro-Oncology

Abstract

Background: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.

Methods: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression was globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell proliferation assays, neurosphere formation, limited dilution assay, and intracranial tumor growth assays were implemented to assess the collaborative capacities of USP36 and ALKBH5 in tumorigenesis.

Results: Ubiquitin-specific peptidase 36 (USP36), as a potential ALKBH5-activating DUB, played an essential role in stabilization of ALKBH5 and regulation of ALKBH5-mediated gene expression in glioblastoma. The depletion of USP36 drastically impaired cell proliferation deteriorated the self-renewal of GSCs and sensitized GSCs to temozolomide (TMZ) treatment. Furthermore, the deletion of USP36 substantially decreased the in vivo tumor growth when monitored by bioluminescence imaging. Our findings indicate that USP36 regulates the protein degradation and expression of ALKBH5, and the USP36-ALKBH5 axis orchestrates glioma tumorigenesis.

Conclusion: Our findings identify USP36 as a DUB of ALKBH5 and its role in glioblastoma progression, which may serve as a potential therapeutic target for glioblastoma treatment.

Keywords

Humans, Glioblastoma, Ubiquitin Thiolesterase, Ubiquitination, Brain Neoplasms, Cell Proliferation, Carcinogenesis, Cell Transformation, Neoplastic, Cell Line, Tumor, AlkB Homolog 5, RNA Demethylase, ALKBH5, USP36, deubiquitination, glioblastoma stem cells

Comments

This article has been corrected. See Neuro Oncol. 2023 Aug 1;25(10):1913.

DOI

10.1093/neuonc/noac238

PMID

36239338

PMCID

PMC10158114

PubMedCentral® Posted Date

10-14-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes