title: Inhibition of human positive cofactor 4 radiosensitizes human esophageal squmaous cell carcinoma cells by suppressing XLF-mediated nonhomologous end joining.
abstract: Radiotherapy has the widest application to esophageal squamous cell carcinoma (ESCC) patients. Factors associated with DNA damage repair have been shown to function in cell radiosensitivity. Human positive cofactor 4 (PC4) has a role in nonhomologous end joining (NHEJ) and is involved in DNA damage repair. However, the clinical significance and biological role of PC4 in cancer progression and cancer cellular responses to chemoradiotherapy (CRT) remain largely unknown. The aim of the present study was to investigate the potential roles of PC4 in the radiosensitivity of ESCC. In this study, we showed that knockdown of PC4 substantially increased ESCC cell sensitivity to ionizing radiation (IR) both in vitro and in vivo and enhanced radiation-induced apoptosis and mitotic catastrophe (MC). Importantly, we demonstrated that silencing of PC4 suppressed NHEJ by downregulating the expression of XLF in ESCC cells, whereas reconstituting the expression of XLF protein in the PC4-knockdown ESCC cells restored NHEJ activity and radioresistance. Moreover, high expression of PC4 positively correlated with ESCC resistance to CRT and was an independent predictor for short disease-specific survival of ESCC patients in both of our cohorts. These findings suggest that PC4 protects ESCC cells from IR-induced death by enhancing the NHEJ-promoting activity of XLF and could be used as a novel radiosensitivity predictor and a promising therapeutic target for ESCCs.
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: D
authors.initials: D
authors.lastname: Qian
authors.affiliation: Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Zeng
authors.affiliation: Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Le Blanc
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Xue
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: H-H
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: T-S
authors.initials: TS
authors.lastname: Zhao
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: M-B
authors.initials: MB
authors.lastname: Meng
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Zhao
authors.affiliation: Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: J-H
authors.initials: JH
authors.lastname: Hao
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: D
authors.initials: D
authors.lastname: Xie
authors.affiliation: 1] Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China [2] Department of Radiation Oncology, Bodine Cancer Center, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Yuan
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D059766:DNA End-Joining Repair / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015536:Down-Regulation / Q000528:radiation effects; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D020868:Gene Silencing / Q000528:radiation effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008938:Mitosis / Q000528:radiation effects; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; C509201:SUB1 protein, human; D014157:Transcription Factors; D045643:DNA Repair Enzymes