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The c-Myc Oncogene Directly Induces the H19 Noncoding RNA by Allele-Specific Binding to Potentiate Tumorigenesis

Divisions of ¹ Cancer Genomics and Proteomics, ² Signaling Biology, and ³ Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital; Departments of ⁴ Medical Biophysics and ⁵ Laboratory Medicine and Pathobiology, ⁶ Computer Science, University of Toronto, Canada; and ⁷ Fred Litwin Cancer Genetics Center, Samuel Lunenfeld Research Institute Mount Sinai Hospital, Toronto, Ontario, Canada

Requests for reprints: Linda Z. Penn, Division of Cancer Genomics and Proteomics, Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, Canada M5G 2M9. Phone: 416-946-2276; Fax: 416-946-2840; E-mail: lpenn{at}uhnres.utoronto.ca.

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. (Cancer Res 2006; 66(10): 5330-7)

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