title: Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model.
abstract: OBJECTIVE
  New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12Dmouse, a model of anaplastic thyroid cancer.
  
  
  METHODS
  We treated ThrbPV/PVKrasG12Dmice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression.
  
  
  RESULTS
  JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation.
  
  
  CONCLUSIONS
  These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430-40. ©2016 AACR.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Enomoto
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yuelin J
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.affiliation: Laboratory Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland. chengs@mail.nih.gov.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D050699:E2F3 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D051379:Mice; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D050699:E2F3 Transcription Factor; D007457:Iodine Radioisotopes; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D037042:Thyroid Hormone Receptors beta; D014230:Triazoles; C561695:(+)-JQ1 compound; C098319:E2F3 protein, human; C117307:KRAS protein, human; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins; C495900:CDK4 protein, human