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Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis

Wiederschain, Dmitri and Chen, Lin and Johnson, Brett and Bettano, Kimberly and Jackson, Dowdy and Taraszka, John and Wang, Y Karen and Jones, Michael and Morrissey, Michael and Deeds, James and Mosher, Rebecca and Fordjour, Paul and Lengauer, Christoph and Benson, John (2007) Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis. Molecular and Cellular Biology, 27 (13). pp. 4968-4979. ISSN 0270-7306

Abstract

Bmi-1 and Mel-18 are structural homologues that belong to the Polycomb group of transcriptional regulators and are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. While a number of clinical and experimental observations have implicated Bmi-1 in human tumorigenesis, the role of Mel-18 in cancer cell growth has not been investigated. We report here that short hairpin RNA-mediated knockdown of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival, anchorage-independent growth, and suppression of tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increases the clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone does not affect the growth of normal human WI38 fibroblasts. Proteomics-based characterization of Bmi-1 and Mel-18 protein complexes isolated from cancer cells revealed substantial similarities in their respective compositions. Finally, gene expression analysis identified a number of cancer-relevant pathways that may be controlled by Bmi-1 and Mel-18 and also showed that these Polycomb proteins regulate a set of common gene targets. Taken together, these results suggest that Bmi-1 and Mel-18 may have overlapping functions in cancer cell growth.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); but on personal or university-hosted websites only
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1907

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