MAGED4B Promotes Glioma Progression via Inactivation of the TNF-α-induced Apoptotic Pathway by Down-regulating TRIM27 Expression

MAGED4B belongs to the melanoma-associated antigen family;originally found in melanoma,it is expressed in various types of cancer,and is especially enriched in glioblastoma.However,the functional role and molecular mechanisms of MAGED4B in glioma are still unclear.In this study,we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue,and the level was positively correlated with glioma grade,tumor diameter,Ki-67 level,and patient age.The patients with higher levels had a worse prognosis than those with lower MAGED4B levels.In glioma cells,MAGED4B overexpression promoted proliferation,invasion,and migration,as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide.On the contrary,MAGED4B knockdown in glioma cells inhibited proliferation,invasion,and migration,as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide.MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain.The interaction between MAGED4B and tripartite motif-containing 27(TRIM27)in glioma cells was detected by co-immunoprecipitation assay,which showed that MAGED4B was co-localized with TRIM27.In addition,MAGED4B overexpression down-regulated the TRIM27 protein level,and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine(MG132),an inhibitor of the proteasome.On the contrary,MAGED4B knockdown up-regulated the TRIM27 level.Furthermore,MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132.Accordingly,MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7(USP7)involved in the tumor necrosis factor-alpha(TNF-α)-induced apoptotic pathway.These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1(RIP1)-dependent TNF-α-induced apoptotic pathway,which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.