title: Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer.
abstract: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated.
  
  
  
  To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models.
  
  
  
  We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells.
  
  
  
  JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling.
  
  
  
  These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Enomoto
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Sunmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Yuelin J
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida 32224.
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.affiliation: Laboratory of Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009361:Neoplasm Invasiveness; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles