title: KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1.
abstract: The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelial-mesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. ©2016 AACR.
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Yu
authors: Y
authors: Gao
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Hongzhao
authors: H
authors: Li
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Xin
authors: X
authors: Ma
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Yang
authors: Y
authors: Fan
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Dong
authors: D
authors: Ni
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Yu
authors: Y
authors: Zhang
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Qingbo
authors: Q
authors: Huang
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Kan
authors: K
authors: Liu
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Xintao
authors: X
authors: Li
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Lei
authors: L
authors: Wang
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Liangyou
authors: L
authors: Gu
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Yuanxin
authors: Y
authors: Yao
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Qing
authors: Q
authors: Ai
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Qingshan
authors: Q
authors: Du
authors: Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors: Erlin
authors: E
authors: Song
authors: Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China. xzhang@tjh.tjmu.edu.cn.|State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, PR China.
authors: Xu
authors: X
authors: Zhang
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000096:biosynthesis*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins