NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma.
Studies support the importance of microRNAs in physiological and pathological processes. Here we describe the regulation and function of miR-29 in myogenesis and rhabdomyosarcoma (RMS). Results demonstrate that in myoblasts, miR-29 is repressed by NF-kappaB acting through YY1 and the Polycomb group. During myogenesis, NF-kappaB and YY1 downregulation causes derepression of miR-29, which in turn accelerates differentiation by targeting its repressor YY1. However, in RMS cells and primary tumors that possess impaired differentiation, miR-29 is epigenetically silenced by an activated NF-kappaB-YY1 pathway. Reconstitution of miR-29 in RMS in mice inhibits tumor growth and stimulates differentiation, suggesting that miR-29 acts as a tumor suppressor through its promyogenic function. Together, these results identify a NF-kappaB-YY1-miR-29 regulatory circuit whose disruption may contribute to RMS.
Wang
Huating
H
Department of Molecular Virology, Human Cancer Genetics Program, The Ohio State University, Columbus, OH 43210, USA.
Garzon
Ramiro
R
Sun
Hao
H
Ladner
Katherine J
KJ
Singh
Ravi
R
Dahlman
Jason
J
Cheng
Alfred
A
Hall
Brett M
BM
Qualman
Stephen J
SJ
Chandler
Dawn S
DS
Croce
Carlo M
CM
Guttridge
Denis C
DC
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D015536:Down-Regulation; D025461:Feedback, Physiological; D005347:Fibroblasts; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D024510:Muscle Development / Q000502:physiology*; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D035683:MicroRNAs; D016328:NF-kappa B; D050986:YY1 Transcription Factor