title: Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.
abstract: Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China ; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China ; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Xinpei
authors.initials: X
authors.lastname: Ci
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA ; Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Dong
authors.affiliation: Department of Biology, University of Oklahoma, Norman, OK, USA.
authors.forename: Zhao-Zhe
authors.initials: ZZ
authors.lastname: Hao
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China ; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase