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

被引:413
作者
Barsyte-Lovejoy, Dalia
Lau, Suzanne K.
Boutros, Paul C.
Khosravi, Fereshteh
Jurisica, Igor
Andrulis, Irene L.
Tsao, Ming S.
Penn, Linda Z.
机构
[1] Princess Margaret Hosp, Ontario Canc Inst, Div Canc Genom & Proteom, Toronto, ON M5G 2M9, Canada
[2] Princess Margaret Hosp, Ontario Canc Inst, Div Signaling Biol, Toronto, ON M5G 2M9, Canada
[3] Princess Margaret Hosp, Ontario Canc Inst, Div Appl Mol Oncol, Toronto, ON M5G 2M9, Canada
[4] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[5] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
[6] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada
[7] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred Litwin Canc Genet Ctr, Toronto, ON M5G 1X5, Canada
关键词
D O I
10.1158/0008-5472.CAN-06-0037
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 H-19 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.
引用
收藏
页码:5330 / 5337
页数:8
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