UCHL5 inhibits U251 glioma cell proliferation and tumor growth via stabilizing and deubiquitinating PTEN

Glioma is the most common primary brain tumor.Exploration of new tumorigenesis mechanism of glioma is critical to determine more effective treatment targets as well as to develop effective prognosis methods that can enhance the treatment efficacy.We previously demonstrated that the deubiquitinase biquitin carboxyl-terminal hydrolase L5(UCHL5)was downregulated in human glioma.However,the effect and mechanism of UCHL5 on the proliferation of glioma cells remains unknown.Methods:Transfection of siRNA was used to knockdown the expression of UCHL5 in U251 cells.The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay,Edu assay,and colony formation assay were employed to identify the effect of UCHL5 on the proliferation of U251 glioma cells.Western blotting and quantitative real-time PCR were carried out to detect the interaction of UCHL5 and PTEN.The effect of UCHL5 on the growth of glioma in vivo was evaluated in nude mice.Then Immunohistochemistry(IHC)were performed to analysis the expression of UCHL5 and PTEN in human glioma tissues.Results:Here,we have reported that silencing of UCHL5 could promote the proliferation of U251 glioma cells through MTT assay,Edu assay,and colony formation assay.Mechanically,we revealed that UCHL5 stabilizes the phosphatase and tensin homolog(PTEN)expression by deubiquitination,thereby inhibiting cell proliferation in U251 cells.Tumor xenograft experiments further demonstrated that silencing the UCHL5 expression could accelerate U251 cell growth in vivo.Finally,in human glioma tissue microarray,the positive correlation between UCHL5 and PTEN expression was confirmed through IHC assay.Conclusion:UCHL5 restrains the proliferation of U251 glioma cells by stabilizing and deubiquitinating PTEN.Our findings provide ideas for developing enhanced targeted PTEN therapy for patients with glioma.

MEF2C promotes M1 macrophage polarization and Th1 responses

The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammation and host defense;however,the underlying molecular mechanism remains unclear.Here,we show that myocyte enhancer factor 2 C(MEF2C)is essential for regulating M1 macrophage polarization in response to infection and inflammation.Global gene expression analysis demonstrated that MEF2C deficiency in macrophages downregulated the expression of M1 phenotypic markers and upregulated the expression of M2 phenotypic markers.MEF2C significantly promoted the expression of interleukin-12 p35 subunit(Il12a)and interleukin-12 p40 subunit(Il12b).Myeloid-specific Mef2c-knockout mice showed reduced IL-12 production and impaired Th1 responses,which led to susceptibility to Listeria monocytogenes infection and protected against DSS-induced IBD in vivo.Mechanistically,we showed that MEF2C directly activated the transcription of Il12a and Il12b.These findings reveal a new function of MEF2C in macrophage polarization and Th1 responses and identify MEF2C as a potential target for therapeutic intervention in inflammatory and autoimmune diseases.