title: The BET bromodomain inhibitor JQ1 radiosensitizes non-small cell lung cancer cells by upregulating p21.
abstract: Radiotherapy is an important treatment modality in the management of locally advanced non-small cell lung cancer (NSCLC). However, radioresistance markedly impairs its efficacy in clinic. Bromodomain and extra-terminal (BET) bromodomain inhibitors have demonstrated dramatic antitumor activity in several preclinical human cancer models. In this study, we investigated for the first time the effect of JQ1, a novel BET bromodomain inhibitor, on tumor cell radiosensitivity of NSCLC in vitro and in vivo. Our results demonstrated that JQ1 significantly enhanced the effect of irradiation in NSCLC cell lines through a c-myc-independent mechanism. The notable findings in response to this combined treatment were prolonged delay in IR-induced DNA double-strand break (DSB) repair, induced robust G2/M checkpoint arrest and increased cell apoptosis. Additional investigations revealed that induction of p21 played an important role in its radiosensitizing effects. In conclusion, these results suggested that BET bromodomain inhibition might offer a potential strategy for enhancing the effects of radiotherapy and reducing radioresistance.
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Mei
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453000, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China. Electronic address: 15827130393@163.com.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000818:Animals; D001381:Azepines / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011836:Radiation Tolerance; D014230:Triazoles / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D014230:Triazoles
keywords: BET bromodomain inhibitor; JQ1; Non-small cell lung cancer; Radiosensitization