The goals of the previous funding period were to map, clone, and characterize a tumor suppressor gene at 13q21 in prostate cancer. In 9 papers including 7 published and 2 submitted, we identified the transcription factor KLF5 as a strong candidate for the 13q21 gene, and demonstrated three mechanisms that inactivate KLF5 in cancer cells, including genomic deletion, transcriptional downregulation, and excessive protein degradation. In addition, we found that KLF5 is an indispensable component of the TGFbeta signaling pathway;and that a ubiquitin E3 ligase that ubiquitinates and degrades KLF5, WWP1, is often overexpressed via copy number gain at 8q21 in prostate cancer, which is responsible for excessive degradation of KLF5 in cancer cells. Furthermore, it has been shown that VWVP1 negatively regulates the TGFbeta signaling pathway by inducing the degradation of Smad2, Smad4, and TGFbeta receptor type I. We therefore hypothesize that overexpression of the E3 ligase WWP1 in epithelial cells causes excessive protein degradation of KLF5 and other components of the TGFbeta signaling pathway, and thus makes cells resistant to the inhibitory effect of TGFbeta in cell proliferation. As a result, cells become more susceptible to other factor-induced carcinogenesis. We will further test and validate this hypothesis in three specific aims. 1) To assess molecular alterations of WWP1 and related molecules in human prostate cancer, clinical cancer specimens will be examined for copy number gain, overexpression, and mutations of WWP1 and for expression change in KLF5 and other components of the TGFbeta pathway. The alterations will be correlated with clinicopathological features of prostate cancer. 2) To examine the function of WWP1 in cell growth in the context of KLF5 and TGFbeta, cells expressing different levels of WWP1 will be examined for growth, cell cycle progression, tumorigenesis, and gene expression changes. 3) To test the role of WWP1 overexpression in carcinogenesis using genetically modified mice, WWP1 will be specifically overexpressed in the prostates of mice. Such mice will be crossed with NKX3.1 and PTEN knockout mice. Phenotypic and molecular alterations will be analyzed in these mice. Completion of these studies will likely show WWP1 to be a molecule useful for developing biomarkers and therapeutic targets as well as for understanding prostate cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087921-10
Application #
7845727
Study Section
Special Emphasis Panel (ZRG1-ONC-J (03))
Program Officer
Hildesheim, Jeffrey
Project Start
2000-08-18
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
10
Fiscal Year
2010
Total Cost
$240,227
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ci, Xinpei; Xing, Changsheng; Zhang, Baotong et al. (2015) KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation. Mol Cancer 14:91
Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong et al. (2014) Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways. Neoplasia 16:883-99
Xing, Changsheng; Fu, Xiaoying; Sun, Xiaodong et al. (2013) Lack of an additive effect between the deletions of Klf5 and Nkx3-1 in mouse prostatic tumorigenesis. J Genet Genomics 40:315-8
Xing, Changsheng; Fu, Xiaoying; Sun, Xiaodong et al. (2013) Different expression patterns and functions of acetylated and unacetylated Klf5 in the proliferation and differentiation of prostatic epithelial cells. PLoS One 8:e65538
Zhao, Ke-Wen; Sikriwal, Deepa; Dong, Xueyuan et al. (2011) Oestrogen causes degradation of KLF5 by inducing the E3 ubiquitin ligase EFP in ER-positive breast cancer cells. Biochem J 437:323-33
Guo, Peng; Dong, Xue-Yuan; Zhao, Ke-Wen et al. (2010) Estrogen-induced interaction between KLF5 and estrogen receptor (ER) suppresses the function of ER in ER-positive breast cancer cells. Int J Cancer 126:81-9
Guo, Peng; Dong, Xue-Yuan; Zhang, Xiaohui et al. (2009) Pro-proliferative factor KLF5 becomes anti-proliferative in epithelial homeostasis upon signaling-mediated modification. J Biol Chem 284:6071-8
Guo, Peng; Zhao, Ke-Wen; Dong, Xue-Yuan et al. (2009) Acetylation of KLF5 alters the assembly of p15 transcription factors in transforming growth factor-beta-mediated induction in epithelial cells. J Biol Chem 284:18184-93
Chen, C; Sun, X; Guo, P et al. (2007) Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Oncogene 26:2386-94
Chen, Ceshi; Zhou, Zhongmei; Ross, Jeffrey S et al. (2007) The amplified WWP1 gene is a potential molecular target in breast cancer. Int J Cancer 121:80-87

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