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.
Highlights
Allele-specific methylation of CpG dinucleotides in the imprinting control region (ICR) leads to H19 expression from the maternal allele, whereas the reciprocally imprinted insulin-like growth factor 2 (IGF2) gene is expressed from the paternal allele [26]
Based on allelic expression and genomic binding studies, we show that c-Myc directly binds to the H19 promoter and highly up-regulates the transcription of the maternal H19 allele by recruiting histone acetyltransferase (HAT) activity
We further show that H19 knockdown, in a panel of breast and lung cancer cell lines, results in the reduction of their tumorigenic phenotype as shown by foci formation and anchorage-independent growth assays
Summary
The transforming members of the Myc family (c-Myc, N-Myc, and L-Myc) show deregulated expression in a broad spectrum of cancers, including carcinomas of the lung, breast, and prostate as well as leukemias and lymphomas [1]. c-Myc is a transcription factor that, with its obligate heterodimerization partner Max, binds to DNA sequence elements called E-boxes [2]. c-Myc-Max can subsequently recruit histone acetyltransferase (HAT) activity [3], chromatin remodeling complexes [4], or promote RNA polymerase II (RNAPII) clearance [5] to allow for target gene transcription. c-Myc-Max can repress gene transcription primarily by interfering with the assembly or function of the transcriptionalNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-0037 complex [6,7,8]. C-Myc regulates numerous gene targets that subsequently execute its many biological activities, including cell proliferation, transformation, angiogenesis, and apoptosis [9]. Identifying these target genes is key in elucidating the role of this potent oncogene in transformation and has received much attention. Recent analyses using advanced high-throughput chromatin immunoprecipitation technology has revealed the nature of the target genes whose promoter regulatory regions are bound by c-Myc [12,13,14,15] These analyses have indicated that c-Myc target genes include both coding and noncoding RNAs To determine the role of c-Mycregulated ncRNAs in transformation, we investigated both the regulation and function of the large prototypic ncRNA, H19, as a downstream target of c-Myc
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