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

Abstract

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 anti-tumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined anti-tumor 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-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.

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

“…Aberrant up-regulation of any MYC family member (MYC, MYCN, or MYCL) promotes metabolic reprograming that leads to sustained proliferation of cancer cells (Brodeur et al 1984;Nau et al 1985;Hatton et al 1996;Beroukhim et al 2010;Liu et al 2012;Hsieh et al 2015). Because MYC is a universal oncogene, there have been several attempts to develop inhibitors that block MYC functions specifically in tumors (Soucek et al 1998;Filippakopoulos et al 2010;Hurlin 2013;Hart et al 2014;McKeown and Bradner 2014;Abedin et al 2016;Alghamdi et al 2016;Zhu et al 2017). However, MYC is still considered an undruggable protein (McKeown and Bradner 2014).…”

Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

“…Bromodomain and extraterminal domain (BET)‐family proteins, which include BRD2, BRD3, BRD4 and BRDT, are epigenetic reader proteins that bind to acetylated‐lysine residues on histones and promote gene transcription by interacting with positive transcription elongation factor b (P‐TEFb) and RNA polymerase II . BET inhibitors bind to BET proteins’ (predominantly BRD4's) recognition pocket for acetylated‐lysine residues and thereby inhibit BET‐histone binding and recruitment of transcriptional complexes to genomic loci, and the results of preclinical studies have indicated that BET inhibitors are broadly active in different cancer types, including NSCLC . Although the effect of BET inhibitors on the expression of oncogenes such as c‐Myc has been extensively addressed, the mechanisms by which BET inhibition produces cytotoxicity remain unknown.…”

“…[3][4][5] BET inhibitors bind to BET proteins' (predominantly BRD4's) recognition pocket for acetylated-lysine residues and thereby inhibit BET-histone binding and recruitment of transcriptional complexes to genomic loci, 6,7 and the results of preclinical studies have indicated that BET inhibitors are broadly active in different cancer types, including NSCLC. [8][9][10][11][12][13] Although the effect of BET inhibitors on the expression of oncogenes such as c-Myc has been extensively addressed, 10,14 the mechanisms by which BET inhibition produces cytotoxicity remain unknown. However, several recent studies have reported that BRD4 is essential for the repair of DNA double-strand breaks (DSBs), and that BET inhibitors suppress both of the major DSB repair mechanisms, homologous recombination (HR) and nonhomologous end joining (NHEJ).…”

Transcriptional targeting of oncogene addiction in medullary thyroid cancer

“…BRD4 inhibitors that displace the BET bromodomain from chromatin also have progressed in preclinical models. In thyroid cancer, mouse anaplastic thyroid cancer models are sensitive to BRD4 inhibition and show reduced tumor burden and suppression of MYC expression (43)(44)(45).…”