title: KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation.
abstract: BACKGROUND
  KLF5 is a basic transcriptional factor that regulates multiple physiopathological processes. Our recent study showed that deletion of Klf5 in mouse prostate promotes tumorigenesis initiated by the deletion of Pten. While molecular characterization of Klf5-null tumors suggested that angiogenesis was partially responsible for tumor promotion, the precise function and mechanism of KLF5 deletion in prostate tumor angiogenesis remain unclear.
  
  
  RESULTS
  Applying histological staining to Pten-null mouse prostates, we observed that deletion of Klf5 significantly increased the number of microvessels, accompanied by the upregulation of multiple angiogenesis-related genes based on microarray analysis with MetaCore software. In human umbilical vein endothelial cells (HuVECs), tube formation and migration, both of which are indicators of angiogenic activities, were decreased by conditioned media from PC-3 and DU 145 human prostate cancer cells with KLF5 overexpression, but increased by media from cells with KLF5 knockdown. HIF1α, a key angiogenesis inducer, was upregulated by KLF5 loss at the protein but not the mRNA level in both mouse tissues and human cell lines, as determined by immunohistochemical staining, real-time RT-PCR and Western blotting. Consistently, KLF5 loss also upregulated VEGF and PDGF, two pro-angiogenic mediators of HIF1α function, as analyzed by immunohistochemical staining in mouse tissues and ELISA in conditioned media. Mechanistically, AKT activity, which caused the accumulation of HIF1α, was increased by KLF5 knockout or knockdown but decreased by KLF5 overexpression. PI3K/AKT inhibitors consistently abolished the effects of KLF5 knockdown on angiogenic activity, HIF1α accumulation, and VEGF and PDGF expression.
  
  
  CONCLUSIONS
  KLF5 loss enhances tumor angiogenesis by attenuating PI3K/AKT signaling and subsequent accumulation of HIF1α in PTEN deficient prostate tumors.
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China. cixinpei@126.com.|Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. cixinpei@126.com.
authors.forename: Xinpei
authors.initials: X
authors.lastname: Ci
authors.affiliation: Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. hunterxcs85@gmail.com.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. baotong.zhang@emory.edu.
authors.forename: Baotong
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. zzhang8@mdanderson.org.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. jianping.jenny.ni@emory.edu.
authors.forename: Jenny Jianping
authors.initials: JJ
authors.lastname: Ni
authors.affiliation: Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. wzhou2@emory.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China. j.dong@emory.edu.|Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, 30322, USA. j.dong@emory.edu.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492214:KLF5 protein, human; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase