title: Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis.
abstract: Cullin-RING ligases (CRLs) are a family of E3 ubiquitin ligase complexes that rely on either RING-box 1 (RBX1) or sensitive to apoptosis gene (SAG), also known as RBX2, for activity. RBX1 and SAG are both overexpressed in human lung cancer; however, their contribution to patient survival and lung tumorigenesis is unknown. Here, we report that overexpression of SAG, but not RBX1, correlates with poor patient prognosis and more advanced disease. We found that SAG is overexpressed in murine KrasG12D-driven lung tumors and that Sag deletion suppressed lung tumorigenesis and extended murine life span. Using cultured lung cancer cells, we showed that SAG knockdown suppressed growth and survival, inactivated both NF-κB and mTOR pathways, and resulted in accumulation of tumor suppressor substrates, including p21, p27, NOXA, and BIM. Importantly, growth suppression by SAG knockdown was partially rescued by simultaneous knockdown of p21 or the mTOR inhibitor DEPTOR. Treatment with MLN4924, a small molecule inhibitor of CRL E3s, also inhibited the formation of KrasG12D-induced lung tumors through a similar mechanism involving inactivation of NF-κB and mTOR and accumulation of tumor suppressor substrates. Together, our results demonstrate that Sag is a Kras-cooperating oncogene that promotes lung tumorigenesis and suggest that targeting SAG-CRL E3 ligases may be an effective therapeutic approach for Kras-driven lung cancers.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Mingjia
authors.initials: M
authors.lastname: Tan
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
authors.forename: Dongping
authors.initials: D
authors.lastname: Wei
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Dafydd
authors.initials: D
authors.lastname: Thomas
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality; D008297:Male; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C118307:RNF7 protein, human; D044767:Ubiquitin-Protein Ligases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins