The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis.
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.
Barsyte-Lovejoy
Dalia
D
Division of Cancer Genomics and Proteomics, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, Canada.
Lau
Suzanne K
SK
Boutros
Paul C
PC
Khosravi
Fereshteh
F
Jurisica
Igor
I
Andrulis
Irene L
IL
Tsao
Ming S
MS
Penn
Linda Z
LZ
D000107:Acetylation; D000483:Alleles; D000818:Animals; D001940:Breast / Q000378:metabolism / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016259:Genes, myc / Q000502:physiology*; D018392:Genomic Imprinting; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D014158:Transcription, Genetic; D015854:Up-Regulation
C094335:H19 long non-coding RNA; D006657:Histones; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II