title: BET protein inhibitor JQ1 attenuates Myc-amplified MCC tumor growth in vivo.
abstract: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus, we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by using the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathologic c-Myc activation. Moreover, JQ1 potently abrogates c-Myc expression in MCC cells and causes marked G1 cell-cycle arrest. Mechanistically, JQ1-induced cell-cycle arrest coincides with downregulation of cyclin D1 and upregulation of p21, p27, and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27, or p57 by shRNA partially protects cells from JQ1-induced cell-cycle arrest. In addition, c-Myc knockdown by shRNA generates significant cell-cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence, indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc.
authors.affiliation: Critical Care Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Critical Care Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Stack
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: James Y
authors.initials: JY
authors.lastname: Suen
authors.affiliation: Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. LGao@uams.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy* / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles