Abstract LB-50: TRIM3, the human homolog of Drosophila Brat, is a tumor suppressor that regulates asymmetric cell division (ACD) in glioblastoma stem cells

2014
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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 cell and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell divisionby developing neural cells and results in a massively enlarged brain composed of neuroblastswith neoplastic properties. Brat promotes asymmetric cell divisionand 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 divisionand stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurospherecultures 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 neurosphereformation and the expression of stem cell markersCD133, Nestinand 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 neurospheresand 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. Citation Format: Subhas Mukherjee, Gang Chen, Monika Anand, Jun Kong, Carol Tucker-Burden, Yuan Rong, Fahmia Rahman, Carlos Moreno, Erwin Van Meir, Constantinos Hadjipanayis, Daniel Brat. TRIM3, the human homolog of Drosophila Brat, is a tumor suppressor that regulates asymmetric cell division(ACD) in glioblastoma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-50. doi:10.1158/1538-7445.AM2014-LB-50
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