BMI-1 Promotes Ewing Sarcoma Tumorigenicity Independent ofCDKN2ARepression

Abstract

Deregulation of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we have investigated if the Ewing sarcoma family of tumors (ESFT) expresses BMI-1 and whether it functions as an oncogene in this highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by ESFT cells and that, although it does not significantly affect proliferation or survival, BMI-1 actively promotes anchorageindependent growth in vitro and tumorigenicity in vivo. Moreover, we find that BMI-1 promotes the tumorigenicity of both p16 wild-type and p16-null cell lines, demonstrating that the mechanism of BMI-1 oncogenic function in ESFT is, at least in part, independent of CDKN2A repression. Expression profiling studies of ESFT cells following BMI-1 knockdown reveal that BMI-1 regulates the expression of hundreds of downstream target genes including, in particular, genes involved in both differentiation and development as well as cell-cell and cell-matrix adhesion. Gain and loss of function assays confirm that BMI-1 represses the expression of the adhesion-associated basement membrane protein nidogen 1. In addition, although BMI-1 promotes ESFT adhesion, nidogen 1 inhibits cellular adhesion in vitro. Together, these data support a pivotal role for BMI-1 ESFT pathogenesis and suggest that its oncogenic function in these tumors is in part mediated through modulation of adhesion pathways. [Cancer Res 2008;68(16):6507-15]

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

“…27 Likewise, there existed no overlapping genes between the current expression profile and the 101 commonly regulated genes following BMI1 knockdown between medulloblastoma and Ewing sarcoma cells. 33,34 In contrast, we detected several genes down-regulated following Bmi1-overexpression in hepatic stem/progenitor cells which are also regulated by Bmi1 in hematopoietic stem/progenitor cells (data not shown). These findings support the fact that PcG proteins function in a cell type-specific manner and the composition of PcG complexes is highly dynamic and differs in different cell-types and even at different gene loci.…”

Cytoplasmic Poly(A) Binding Protein C4 Serves a Critical Role in Erythroid Differentiation

“…A total of 4,850 curated gene sets were mined utilizing gene set enrichment analysis (GSEA) (42, 43) with a filter set for a false discovery rate (FDR) Q value of Ͻ0.25. The gene sets identified in this analysis overlapped four pathways (in rank order); hematopoietic stem cell differentiation (P ϭ 0.0005) (44), oxidative phosphorylation (P ϭ 0.043) (42), nasopharyngeal carcinoma (P ϭ 0.025), and Ewing sarcoma (P ϭ 0.016) (45,46). Importantly, this group of 31 RNAs contained two globin RNAs, Hba-a1 and Hba-a2.…”

Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells

“…Several studies have been carried out on this issue in different cancertypes, such as glioma, medulloblastoma and sarcoma. [24][25][26] Our findings have added a new set of potential target genes to the list. …”