title: Loss of KLF14 triggers centrosome amplification and tumorigenesis.
abstract: Centrosome amplification is frequent in cancer, but the underlying mechanisms remain unclear. Here we report that disruption of the Kruppel-like factor 14 (KLF14) gene in mice causes centrosome amplification, aneuploidy and spontaneous tumorigenesis. Molecularly, KLF14 functions as a transcriptional repressor of Plk4, a polo-like kinase whose overexpression induces centrosome overduplication. Transient knockdown of KLF14 is sufficient to induce Plk4-directed centrosome amplification. Clinically, KLF14 transcription is significantly downregulated, whereas Plk4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and Plk4 protein expression in human breast and colon cancers. Moreover, KLF14 depletion promotes AOM/DSS-induced colon tumorigenesis. Our findings reveal that KLF14 reduction serves as a mechanism leading to centrosome amplification and tumorigenesis. On the other hand, forced expression of KLF14 leads to mitotic catastrophe. Collectively, our findings identify KLF14 as a tumour suppressor and highlight its potential as biomarker and therapeutic target for cancer.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.|Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Songjiang District, Shanghai 201620, China.
authors.forename: Guangjian
authors.initials: G
authors.lastname: Fan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.|Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Songjiang District, Shanghai 201620, China.
authors.forename: Lianhui
authors.initials: L
authors.lastname: Sun
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.|Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Songjiang District, Shanghai 201620, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Shan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xianying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Huan
authors.affiliation: Department of Pathology and Cell Biology, USF Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Gu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Yao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Shanxi 030001, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University, Shenyang 110000, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Songjiang District, Shanghai 201620, China.
authors.forename: Shengping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.|Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Songjiang District, Shanghai 201620, China.|Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University, Shenyang 110000, China.
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051703:Sp Transcription Factors / Q000235:genetics*
chemical_list: C417549:KLF14 protein, human; C558181:Klf14 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D051703:Sp Transcription Factors; C490219:PLK4 protein, human; C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases