MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas Journal Article
| Authors: | Huang, R.; Cheung, N. K. V.; Vider, J.; Cheung, I. Y.; Gerald, W. L.; Tickoo, S. K.; Holland, E. C.; Blasberg, R. G. |
| Article Title: | MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas |
| Abstract: | The BMI1 gene is overexpressed in ∼90% of human neuroblastomas. However, little is known about the regulation of BMI1 expression. Using microarray and immunohistochemical analysis, we show that BMI1 expression correlated with MYCN levels in MYCN-amplified human neuroblastomas, and with MYC levels in the MYCN-nonamplified group. We further demonstrated that BMI1 is a direct target gene of MYCN/MYC in 3 neuroblastoma cell lines: BE (2)-C, LAN1, and SH-SY5Y. Overexpression of MYCN or MYC transactivated the BMI1 promoter and up-regulated BMI1 gene expression. shRNA-mediated knockdown of MYCN or MYC decreased BMI1 gene expression. Chromatin immunoprecipitation and pointmutation assays revealed that both MYCN and MYC bind to the E-box within the BMI1 promoter. Overexpression of BMI1, MYCN, and MYC independently increased both cell proliferation and tumor growth. Conversely, specific inhibition of BMI1, MYCN, and MYC decreased tumor cell proliferation and tumor growth. Interestingly, BMI1 suppression in MYCN/ MYC-overexpressing cells resulted in significantly greater inhibition compared to that in mock-transduced and parental cells. Our results indicate that MYCN and MYC regulate BMI1 gene expression at the transcriptional level and that dysregulation of the BMI1 gene mediated by MYCN or MYC overexpression, confers increased cell proliferation during neuroblastoma genesis and tumor progression. © FASEB. |
| Keywords: | survival; controlled study; human tissue; protein expression; unclassified drug; human cell; proto-oncogene proteins; nonhuman; cell proliferation; mouse; animals; mice; animal tissue; gene expression; animal experiment; animal model; protein binding; rna, small interfering; tumor xenograft; cell line, tumor; mice, inbred balb c; carcinogenesis; nuclear proteins; gene expression regulation, neoplastic; mice, nude; infant; neuroblastoma; chromatin immunoprecipitation; promoter regions, genetic; myc protein; genes, myc; oncogene proteins; carcinogenicity; transplantation, heterologous; upregulation; neoplasm transplantation; tumor growth; point mutation; proto-oncogene proteins c-myc; bmi1 protein; repressor proteins; transcriptional activation; short hairpin rna; gene knockdown techniques; protein mycn; transcriptional regulation; e box element |
| Journal Title: | FASEB Journal |
| Volume: | 25 |
| Issue: | 12 |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2011-12-01 |
| Start Page: | 4138 |
| End Page: | 4149 |
| Language: | English |
| DOI: | 10.1096/fj.11-185033 |
| PROVIDER: | scopus |
| PUBMED: | 21856782 |
| PMCID: | PMC3236625 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 January 2012" - "CODEN: FAJOE" - "Source: Scopus" |
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