title: CPSF4 activates telomerase reverse transcriptase and predicts poor prognosis in human lung adenocarcinomas.
abstract: The elevated expression and activation of human telomerase reverse transcriptase (hTERT) is associated with the unlimited proliferation of cancer cells. However, the excise mechanism of hTERT regulation during carcinogenesis is not well understood. In this study, we discovered cleavage and polyadenylation specific factor 4 (CPSF4) as a novel tumor-specific hTERT promoter-regulating protein in lung cancer cells and identified the roles of CPSF4 in regulating lung hTERT and lung cancer growth. The ectopic overexpression of CPSF4 upregulated the hTERT promoter-driven report gene expression and activated the endogenous hTERT mRNA and protein expression and the telomerase activity in lung cancer cells and normal lung cells. In contrast, the knockdown of CPSF4 by siRNA had the opposite effects. CPSF4 knockdown also significantly inhibited tumor cell growth in lung cancer cells in vitro and in a xenograft mouse model in vivo, and this inhibitory effect was partially mediated by decreasing the expression of hTERT. High expression of both CPSF4 and hTERT proteins were detected in lung adenocarcinoma cells by comparison with the normal lung cells. Tissue microarray immunohistochemical analysis of lung adenocarcinomas also revealed a strong positive correlation between the expression of CPSF4 and hTERT proteins. Moreover, Kaplan-Meier analysis showed that patients with high levels of CPSF4 and hTERT expression had a significantly shorter overall survival than those with low CPSF4 and hTERT expression levels. Collectively, these results demonstrate that CPSF4 plays a critical role in the regulation of hTERT expression and lung tumorigenesis and may be a new prognosis factor in lung adenocarcinomas.
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Wangbing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Qin
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China. Electronic address: wangshs@sysucc.org.cn.
authors.forename: Shusen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Fu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Wendan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China. Electronic address: huangwl@sysucc.org.cn.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China. Electronic address: dengwg@sysucc.org.cn.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D039223:Cleavage And Polyadenylation Specificity Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D039223:Cleavage And Polyadenylation Specificity Factor; C509186:TERT protein, human; D019098:Telomerase
keywords: CPSF4; Lung cancer; Promoter; Telomerase; hTERT