The C-myc Oncogene Directly Induces the H19 Noncoding Rna by Allele-specific Binding to Potentiate Tumorigenesis.
From: Division of Cancer Genomics and Proteomics, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, Canada.
Cancer research
- Publish Date: May 2006
- ISSN: 0008-5472
- Volume: 66
- Issue: 10
- Pages: 5330-7
- Medium: Print
- Language: English
- Citation (JAMA): Barsyte-Lovejoy Dalia, Lau Suzanne K, Boutros Paul C, et al. The C-myc Oncogene Directly Induces the H19 Noncoding Rna by Allele-specific Binding to Potentiate Tumorigenesis.. Cancer Res. May 2006;66:5330-7
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 Headings (Keywords): Acetylation, Alleles, Animals, Breast, Breast Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Genes, myc, Genomic Imprinting, Glioblastoma, Histones, Humans, Insulin-Like Growth Factor II, Lung Neoplasms, Promoter Regions (Genetics), Proto-Oncogene Proteins c-myc, RNA, Messenger, RNA, Untranslated, Rats, Transcription, Genetic, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 16707459
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