title: The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling.
abstract: Chondrosarcoma, the second-most frequent primary bone malignancy, is generally more resistant to conventional chemotherapy and radiotherapy. Therefore, the development of an effective adjuvant therapy is necessary. Recently, targeting the epigenetic regulator such as bromodomain and extraterminal domain (BET) proteins has achieved great success. For instance, the bromodomain inhibitor JQ1 has been shown to inhibit the growth of several cancer cells both in vitro and in vivo. Herein, we demonstrated that JQ1 significantly inhibited chondrosarcoma cell growth and colony formation. JQ1 also induced marked G1-phase cell cycle arrest coincided with the up-regulation of p21WAF1/CIP1, p27Kip1, and Cyclin D1 expression, and the down-regulation of Cyclin E2 expression. Moreover, JQ1 induced the premature senescence of SW 1353 cells, and that prolong treatment of JQ1 caused cell apoptosis. Mechanistically, the JQ1-induced cell growth inhibition was correlated with the suppression of c-Myc and Bcl-xL, which are the prime genes for cell cycle control and anti-apoptosis. Furthermore, we demonstrated that p21 negatively regulated the expression of c-Myc and Bcl-xL upon JQ1 treatment, and that the growth inhibition of SW 1353 and Hs 819.T cells and induction of p21 were predominantly regulated by the LATS1/YAP signaling but not through a p53-dependent manner. In conclusion, we disclosed a novel mechanism that JQ1 inhibits cell proliferation, induces cell senescence and apoptosis of chondrosarcoma cells through the regulation of the YAP/p21/c-Myc/Bcl-xL signaling axis. J. Cell. Biochem. 118: 2182-2192, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.|Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Huan-Tian
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Gui
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sang
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
authors.forename: Yu-Hang
authors.initials: YH
authors.lastname: Li
authors.affiliation: The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510240, China.
authors.forename: Gui-Hong
authors.initials: GH
authors.lastname: Liang
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
authors.forename: Thomas
authors.initials: T
authors.lastname: Li
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: He
authors.affiliation: Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
authors.forename: Zhen-Gang
authors.initials: ZG
authors.lastname: Zha
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001381:Azepines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D002813:Chondrosarcoma / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors; D014230:Triazoles / Q000494:pharmacology*; D000091102:YAP-Signaling Proteins; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001381:Azepines; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010750:Phosphoproteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; D000091102:YAP-Signaling Proteins; C561695:(+)-JQ1 compound; C088374:YAP1 protein, human; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
keywords: CELL CYCLE ARREST; CHONDROSARCOMA; JQ1; YAP; p21