MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas Academic Article uri icon

Overview

MeSH Major

  • Genes, myc
  • Neuroblastoma
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins

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 point-mutation 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.

publication date

  • December 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3236625

Digital Object Identifier (DOI)

  • 10.1096/fj.11-185033

PubMed ID

  • 21856782

Additional Document Info

start page

  • 4138

end page

  • 49

volume

  • 25

number

  • 12