title: Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma.
abstract: Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cells and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures, and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin, and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi-Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Biomedical Informatics, Emory University, Atlanta, Georgia.
authors.forename: Jun
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors.forename: Carol
authors.initials: C
authors.lastname: Tucker-Burden
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors.forename: Monika
authors.initials: M
authors.lastname: Anand
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Rong
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors.forename: Fahmia
authors.initials: F
authors.lastname: Rahman
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Department of Biomedical Informatics, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
authors.affiliation: Department of Neurosurgery, Emory University, Atlanta, Georgia. Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.affiliation: Department of Neurosurgery, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Constantinos G
authors.initials: CG
authors.lastname: Hadjipanayis
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia. Department of Biomedical Informatics, Emory University, Atlanta, Georgia. Winship Cancer Institute, Emory University, Atlanta, Georgia. dbrat@emory.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D015398:Signal Transduction; D014162:Transfection
chemical_list: D002352:Carrier Proteins; C426543:TRIM3 protein, human