title: The polyamine catabolic enzyme SAT1 modulates tumorigenesis and radiation response in GBM.
abstract: Glioblastoma multiforme (GBM) is the most common and severe form of brain cancer. The median survival time of patients is approximately 12 months due to poor responses to surgery and chemoradiation. To understand the mechanisms involved in radioresistance, we conducted a genetic screen using an shRNA library to identify genes in which inhibition would sensitize cells to radiation. The results were cross-referenced with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors and associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors, and correlates with poor outcomes. Knockdown of SAT1 using shRNA and siRNA approaches in multiple cell and neurosphere lines resulted in sensitization of GBM cells to radiation in colony formation assays and tumors, and decreased tumorigenesis in vivo. Radiosensitization occurred specifically in G2-M and S phases, suggesting a role for SAT1 in homologous recombination (HR) that was confirmed in a DR-GFP reporter system. Mechanistically, we found that SAT1 promotes acetylation of histone H3, suggesting a new role of SAT1 in chromatin remodeling and regulation of gene expression. In particular, SAT1 depletion led to a dramatic reduction in BRCA1 expression, explaining decreased HR capacity. Our findings suggest that the biologic significance of elevated SAT1 expression in GBM lies in its contribution to cell radioresistance and that SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies.
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Adina
authors.initials: A
authors.lastname: Brett-Morris
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Wright
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio. Department of Radiation Oncology, Osaka University, Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Vinay
authors.initials: V
authors.lastname: Pasupuleti
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Junran
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Applied Sciences, Auckland University of Technology, New Zealand.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Spina
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Eli E
authors.initials: EE
authors.lastname: Bar
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Gujrati
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schur
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio. scott.welford@case.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Welford
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011073:Polyamines / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D006657:Histones; D011073:Polyamines; D034741:RNA, Small Interfering; D000099228:Diamine N-Acetyltransferase