Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model

Clin Cancer Res. 2017 Jan 15;23(2):430-440. doi: 10.1158/1078-0432.CCR-16-0914. Epub 2016 Jul 20.


Purpose: 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/PVKrasG12D mouse, a model of anaplastic thyroid cancer.

Experimental design: We treated ThrbPV/PVKrasG12D mice 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.

MeSH terms

  • Animals
  • Azepines / administration & dosage*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatin Assembly and Disassembly / drug effects
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase 4 / genetics
  • E2F3 Transcription Factor / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Iodine Radioisotopes / administration & dosage*
  • Mice
  • Proteins / antagonists & inhibitors
  • Proteins / genetics*
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Rats
  • Signal Transduction / drug effects
  • Thyroid Hormone Receptors beta / genetics
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology
  • Triazoles / administration & dosage*
  • Xenograft Model Antitumor Assays


  • (+)-JQ1 compound
  • Azepines
  • E2F3 Transcription Factor
  • E2F3 protein, human
  • Iodine Radioisotopes
  • KRAS protein, human
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Thyroid Hormone Receptors beta
  • Triazoles
  • bromodomain and extra-terminal domain protein, human
  • Cyclin D1
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Proto-Oncogene Proteins p21(ras)