Myc: Maestro of MicroRNAs.

Hyperactivity of the Myc oncogenic transcription factor dramatically reprograms gene expression to facilitate cellular proliferation and tumorigenesis. To elicit these effects, Myc coordinates the activation and repression of an extensive network of protein-coding genes and, as has recently been appreciated, noncoding RNAs including microRNAs (miRNAs). Consistent with their ability to potently influence cancer phenotypes, the regulation of miRNAs by Myc affects virtually all aspects of the Myc oncogenic program, including proliferation, survival, metabolism, angiogenesis, and metastasis. This review will summarize the current understanding of the mechanisms underlying Myc-dependent transcriptional and posttranscriptional control of miRNAs and the resultant effects on tumorigenesis. As miRNAs are integral nodes in the transcriptional network controlled by Myc, modulating their activity represents a promising new approach for cancer therapy.

[1]  S. Hammond,et al.  An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells , 2000, Nature.

[2]  Michael A. Beer,et al.  Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation , 2009, Proceedings of the National Academy of Sciences.

[3]  Doron Betel,et al.  Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas. , 2009, Genes & development.

[4]  V. Kim,et al.  Biogenesis of small RNAs in animals , 2009, Nature Reviews Molecular Cell Biology.

[5]  Keara M. Lane,et al.  Dicer1 functions as a haploinsufficient tumor suppressor. , 2009, Genes & development.

[6]  Hiroyuki Tagawa,et al.  Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. , 2004, Cancer research.

[7]  Anton J. Enright,et al.  Annotation of mammalian primary microRNAs , 2008, BMC Genomics.

[8]  Ying Feng,et al.  Supplemental Data P53-mediated Activation of Mirna34 Candidate Tumor-suppressor Genes , 2022 .

[9]  P. Bouillet,et al.  Bim is a suppressor of Myc-induced mouse B cell leukemia. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  B. Cullen,et al.  Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. , 2003, Genes & development.

[11]  D. Iliopoulos,et al.  E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. , 2008, Cancer cell.

[12]  C. Joo,et al.  TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation , 2009, Cell.

[13]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[14]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Lim,et al.  Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression , 2007, Molecular and Cellular Biology.

[16]  Stefanie Dimmeler,et al.  MicroRNA-92a Controls Angiogenesis and Functional Recovery of Ischemic Tissues in Mice , 2009, Science.

[17]  Jing Wang,et al.  Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes , 2008, Nature Immunology.

[18]  A. Caudy,et al.  Argonaute2, a Link Between Genetic and Biochemical Analyses of RNAi , 2001, Science.

[19]  M. Pickering,et al.  miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression , 2009, Oncogene.

[20]  Jeffrey M. Trimarchi,et al.  Transcription: Sibling rivalry in the E2F family , 2002, Nature Reviews Molecular Cell Biology.

[21]  T. Golub,et al.  Impaired microRNA processing enhances cellular transformation and tumorigenesis , 2007, Nature Genetics.

[22]  Anthony Mancuso,et al.  Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction , 2008, Proceedings of the National Academy of Sciences.

[23]  K. Matthay,et al.  Neuroblastoma: Biology and staging , 2009, Current oncology reports.

[24]  G. Wildey,et al.  Evidence That Ser87 of BimEL Is Phosphorylated by Akt and Regulates BimEL Apoptotic Function* , 2006, Journal of Biological Chemistry.

[25]  S. Dangi‐Garimella,et al.  Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let‐7 , 2009, The EMBO journal.

[26]  V. Narry Kim,et al.  Characterization of DGCR8/Pasha, the essential cofactor for Drosha in primary miRNA processing , 2006, Nucleic acids research.

[27]  Kathryn A. O’Donnell,et al.  Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model , 2009, Cell.

[28]  F. Westermann,et al.  MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors , 2010, Oncogene.

[29]  N. Rajewsky,et al.  Dicer Ablation Affects Antibody Diversity and Cell Survival in the B Lymphocyte Lineage , 2008, Cell.

[30]  Moshe Oren,et al.  Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. , 2007, Molecular cell.

[31]  V. Kim,et al.  MicroRNA maturation: stepwise processing and subcellular localization , 2002, The EMBO journal.

[32]  J. M. Thomson,et al.  Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. , 2008, RNA.

[33]  Carla Oliveira,et al.  A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function , 2009, Nature Genetics.

[34]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[35]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  L. Lim,et al.  MicroRNAs in the miR-106b Family Regulate p21/CDKN1A and Promote Cell Cycle Progression , 2008, Molecular and Cellular Biology.

[37]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[38]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[39]  J. Mendell,et al.  Circular reasoning: microRNAs and cell-cycle control. , 2008, Trends in biochemical sciences.

[40]  Daniel E Bauer,et al.  ATP citrate lyase inhibition can suppress tumor cell growth. , 2005, Cancer cell.

[41]  Naoto Tsuchiya,et al.  Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells , 2007, Proceedings of the National Academy of Sciences.

[42]  Jennifer E. Van Eyk,et al.  c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism , 2016 .

[43]  Birgit Samans,et al.  MYCN regulates oncogenic MicroRNAs in neuroblastoma , 2007, International journal of cancer.

[44]  Richard Grundy,et al.  The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. , 2009, Cancer research.

[45]  J. Lovén,et al.  MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma , 2010, Proceedings of the National Academy of Sciences.

[46]  John L Cleveland,et al.  c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. , 2002, Genes & development.

[47]  Patrick J. Paddison,et al.  Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia , 2010, Nature Cell Biology.

[48]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[49]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[50]  Michael A. Beer,et al.  Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. , 2007, Molecular cell.

[51]  E. Furth,et al.  Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster , 2006, Nature Genetics.

[52]  R. Eisenman,et al.  The Myc/Max/Mad network and the transcriptional control of cell behavior. , 2000, Annual review of cell and developmental biology.

[53]  Jason H. Moore,et al.  Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. , 2007, Cancer research.

[54]  C. Joo,et al.  Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. , 2008, Molecular cell.

[55]  Phillip A Sharp,et al.  Suppression of non-small cell lung tumor development by the let-7 microRNA family , 2008, Proceedings of the National Academy of Sciences.

[56]  R. Russell,et al.  bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila , 2003, Cell.

[57]  R. Eisenman,et al.  Myc's broad reach. , 2008, Genes & development.

[58]  S. Lowe,et al.  miR-19 is a key oncogenic component of mir-17-92. , 2009, Genes & development.

[59]  Andrea Califano,et al.  The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. , 2010, Cancer cell.

[60]  D. Higgins,et al.  Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival , 2009, PloS one.

[61]  Christopher H. Contag,et al.  MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer , 2004, Nature.

[62]  Rudolf Jaenisch,et al.  Targeted Deletion Reveals Essential and Overlapping Functions of the miR-17∼92 Family of miRNA Clusters , 2008, Cell.

[63]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[64]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[65]  S. Kauppinen,et al.  LNA-mediated microRNA silencing in non-human primates , 2008, Nature.

[66]  G. Daley,et al.  Selective Blockade of MicroRNA Processing by Lin28 , 2008, Science.

[67]  Shuji Fujita,et al.  Putative promoter regions of miRNA genes involved in evolutionarily conserved regulatory systems among vertebrates , 2008, Bioinform..

[68]  F. Slack,et al.  Regression of murine lung tumors by the let-7 microRNA , 2009, Oncogene.

[69]  Scott A Gerber,et al.  Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis , 2008, Proceedings of the National Academy of Sciences.

[70]  C. Croce,et al.  MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[71]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[72]  R. Gregory,et al.  Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in embryonic stem cells , 2009, Nature Structural &Molecular Biology.

[73]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[74]  V. Kim,et al.  The nuclear RNase III Drosha initiates microRNA processing , 2003, Nature.

[75]  Wun-Jae Kim,et al.  Cancer gene therapy using adeno-associated virus vectors. , 2008, Frontiers in bioscience : a journal and virtual library.

[76]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[77]  Piotr Sliz,et al.  Determinants of MicroRNA Processing Inhibition by the Developmentally Regulated RNA-binding Protein Lin28* , 2008, Journal of Biological Chemistry.

[78]  R. Gregory,et al.  Many roads to maturity: microRNA biogenesis pathways and their regulation , 2009, Nature Cell Biology.

[79]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[80]  C. Croce,et al.  MiR-15a and miR-16-1 cluster functions in human leukemia , 2008, Proceedings of the National Academy of Sciences.

[81]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[82]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[83]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[84]  Vincent De Guire,et al.  An E2F/miR-20a Autoregulatory Feedback Loop* , 2007, Journal of Biological Chemistry.

[85]  T. Halazonetis,et al.  Genomic instability — an evolving hallmark of cancer , 2010, Nature Reviews Molecular Cell Biology.

[86]  Fedor V. Karginov,et al.  The miR-17∼92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma , 2009, Proceedings of the National Academy of Sciences.

[87]  Frank Speleman,et al.  miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis , 2010, Nature Cell Biology.

[88]  J. Lees,et al.  Life and death decisions by the E2F transcription factors. , 2007, Current opinion in cell biology.

[89]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[90]  Stephanie Roessler,et al.  MicroRNA expression, survival, and response to interferon in liver cancer. , 2009, The New England journal of medicine.

[91]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[92]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[93]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[94]  Huating Wang,et al.  NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. , 2008, Cancer cell.

[95]  L. Smirnova,et al.  A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment , 2008, Nature Cell Biology.

[96]  T. Tuschl,et al.  Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate , 2001, The EMBO journal.

[97]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[98]  B. Carter,et al.  Adeno-associated virus vectors in clinical trials. , 2005, Human gene therapy.

[99]  F. Slack,et al.  The let-7 microRNA reduces tumor growth in mouse models of lung cancer , 2008, Cell cycle.