The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis

Cancer Res. 2006 May 15;66(10):5330-7. doi: 10.1158/0008-5472.CAN-06-0037.

Abstract

The product of the MYC oncogene is widely deregulated in cancer and functions as a regulator of gene transcription. Despite an extensive profile of regulated genes, the transcriptional targets of c-Myc essential for transformation remain unclear. In this study, we show that c-Myc significantly induces the expression of the H19 noncoding RNA in diverse cell types, including breast epithelial, glioblastoma, and fibroblast cells. c-Myc binds to evolutionarily conserved E-boxes near the imprinting control region to facilitate histone acetylation and transcriptional initiation of the H19 promoter. In addition, c-Myc down-regulates the expression of insulin-like growth factor 2 (IGF2), the reciprocally imprinted gene at the H19/IGF2 locus. We show that c-Myc regulates these two genes independently and does not affect H19 imprinting. Indeed, allele-specific chromatin immunoprecipitation and expression analyses indicate that c-Myc binds and drives the expression of only the maternal H19 allele. The role of H19 in transformation is addressed using a knockdown approach and shows that down-regulation of H19 significantly decreases breast and lung cancer cell clonogenicity and anchorage-independent growth. In addition, c-Myc and H19 expression shows strong association in primary breast and lung carcinomas. This work indicates that c-Myc induction of the H19 gene product holds an important role in transformation.

MeSH terms

  • Acetylation
  • Alleles*
  • Animals
  • Breast / metabolism
  • Breast / physiology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Genes, myc / physiology*
  • Genomic Imprinting
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Insulin-Like Growth Factor II / biosynthesis
  • Insulin-Like Growth Factor II / genetics
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Long Noncoding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Untranslated / biosynthesis
  • RNA, Untranslated / genetics*
  • Rats
  • Transcription, Genetic
  • Up-Regulation

Substances

  • H19 long non-coding RNA
  • Histones
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Untranslated
  • Insulin-Like Growth Factor II