Dalia Barsyte-Lovejoy 1, Suzanne K. Lau 3, 4, Paul C. Boutros 1, 2, 4, Fereshteh Khosravi 1, Igor Jurisica 2, 4, 6, Irene L. Andrulis 7, Ming S. Tsao 3, 4, 5, and Linda Z. Penn 1, 4
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;
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@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.
Additional References:
1. Wu S, Meng L, Wang S, Wang W, Xi L, Tian X, Chen G, Wu Y, Zhou
J, Xu G, Lu Y, and Ma D,
"Reversal of the
Malignant Phenotype of Cervical Cancer CaSki Cells through Adeno-Associated
Virus–Mediated Delivery of HPV16 E7 Antisense RNA".
2. Diccianni MB, Calin GA, Ferracin M, Liu C-G, Negrini M, Croce
CM, and Yu A,
"MicroRNA profiles
of childhood T cell acute lymphoblastic leukemia".
3. Avigad S, Hameiri-Grossman M, Cohen IJ, Ash S, Weizman A, and
Yaniv I,
"Frequent deletions
of specific micro-RNAs in Ewing sarcoma".
4. Esquela-Kerscher A, and Slack FJ, "Oncomirs — microRNAs with a role in cancer".
5. Frenster JH, and Hovsepian JA, "Ultrastructure of Euchromatin Contact Points between the Closed Loops of Adjacent Interphase Chromosomes".
6. Xu N, Tsai C-L, Lee JT,
"Transient Homologous
Chromosome Pairing Marks the Onset of X Inactivation".
7. Bacher CP, Guggiari M, Brors B, Augui S, Clerc P, Avner P, Eils
R, and Heard E,
"Transient colocalization
of X-inactivation centres accompanies the initiation of X inactivation".
8. Eder M, and Scherr M, "MicroRNA and Lung Cancer".
9. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, and Slack FJ, "RAS Is Regulated by the let-7 MicroRNA Family".
10. Hovsepian JA, and Frenster JH, "Sense and Antisense during RNA Initiation of the DNA Transcription Bubble".
Links to RNA and Biological Causality:
Links to
Euchromatin Activator RNA Reviews:
Links to
Euchromatin Activator RNA Research:
Links to Ultrastructural
Probes of DNase I-Sensitive Sites:
Links to
RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma
Immuno-Pathology:
Links to Activated
T-Lymphocyte Immunotherapy:
Links to Medical
Systems Biology:
Links to Selective
Gene Transcription:
Links to RNA-Induced
Epigenetics:
Links to RNA-Induced
Embryogenesis:
Links to RNA and
Biological Causality:
Links to Reprogramming
and Neoplasia:
"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".
For Further Information and Feedback:
Phone: +1 650 367 6483
E-mail: frenster@euchromatin.net