USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5

alexandrossfakianakis shared this article with you from Inoreader USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5 via Neuro-Oncology Advance Access 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 were 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 co llaborative 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. View on Web

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