NUSAP1 potentiates chemoresistance in glioblastoma through its SAP domain to stabilize ATR

NUSAP1,which is a microtubule-associated protein involved in mitosis,plays essential roles in diverse biological processes,especially in cancer biology.In this study,NUSAP1 was found to be overexpressed in GBM tissues in a grade-dependent manner compared with normal brain tissues.NUSAP1 was also highly expressed in GBM patients,dead patients,and GBM cells.In addition,NUSAP1 was found to participate in cell proliferation,apoptosis,and DNA damage in GBM cells.Ataxia telangiectasia and Rad3-related protein(ATR)are a primary sensor of DNA damage,and ATR is also a promising target in cancer therapy.Here,we found that NUSAP1 positively regulated the expression of ATR.Mechanistically,NUSAP1 suppressed the ubiquitin-dependent proteolysis of ATR.The SAP(SAF-A/B,Acinus,and PIAS)domain is a common motif of many SUMO(small ubiquitin-like modifier)E3 ligases,and this domain is involved in substrate recognition and ligase activity.This study further demonstrated that the SAP domain of NUSAP1 promoted the sumoylation of ATR,and thereby antagonized the ubiquitination of ATR.These results suggest that NUSAP1 stabilizes ATR by sumoylation.Moreover,NUSAP1 potentiated chemotherapeutic resistance to temozolomide(TMZ)and doxorubicin(DOX)through its SAP domain.Overall,this study indicates that NUSAP1 is a promising therapeutic target in GBM.

Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.