Accumulated evidence has shown a significant role for the Wnt/?-catenin pathway in prostate development and tumorigenesis. Dysregulation of cytoplasmic and nuclear ?-catenin has been demonstrated to be a key event in tumorigenesis. Thus, the significance of ?-catenin in human tumors was corroborated by discoveries of mutations in both ?-catenin and the destruction complex components in tumor cells. More than 80% of colorectal cancers possess inactive mutations in the tumor suppressor, APC. Mutations in axin were also found in hepatocellular carcinomas. Moreover, point mutations within the four serine/threonine residues in the target sites of GSK32 were found in ?-catenin in a wide variety of human malignancies. Intriguingly, mutations in ?-catenin, APC, and other components of the destruction complex are very rare in prostate cancer samples. However, increased nuclear ?-catenin has been frequently observed in advanced prostate cancers during the disease progression. Therefore, other pathways/mechanisms may play a dominant role in the regulation of the Wnt/??-catenin signaling pathway during the course of prostate cancer initiation and progression. In the past, we identified that LAPSER1, also named LZTS2 (leucine zipper putative tumor suppressor 2), is a novel ?-catenin interacting protein. The human LZTS2 gene is located on chromosome 10q24.3. This region has been shown to be frequently lost in a variety of human tumors, including prostate cancer. Over- expression of LZTS2 protein affects the subcellular localization of ?-catenin, represses the transcriptional activity of ?-catenin, and inhibits cell growth. Intriguingly, a functional HIV Rev-like leucine rich, CRM1/exportin regulated nuclear export signal (NES) was identified within the C-terminus of LZTS2. Through this NES site, LZTS2 can enhance the nuclear export of ?-catenin and reduce the level of nuclear ?-catenin in cells. Using immunohistochemistry approaches, we further demonstrated that LZTS2 is expressed in the cytoplasm of luminal epithelial cells of prostate glands, and its expression is significantly reduced in human prostate tumor samples. These data elucidate an important role for LZTS2 as a novel regulator in Wnt/??-catenin-mediated transcription, cell growth, and tumorigenesis. Although a critical role for the Wnt/??-catenin signaling pathway has been established in prostate tumorigenesis, the precise pathways/mechanisms underlying the dysregulation of??-catenin in prostate cancer cells still remain unclear. Our recent findings that LZTS2 is a ?-catenin interacting protein and modulates the activity and cellular localization of ?-catenin point to LZTS2 as a novel regulator for the Wnt/??-catenin signaling pathway Therefore, we propose a series of experiments in this revised RO1 application to address our central hypothesis that LZTS2 negatively regulates the Wnt/??-catenin signaling pathway and its dysregulation will activate the Wnt/??-catenin signaling pathway and contribute to tumorigenesis.
Three specific aims are proposed as follows: 1) characterizing the biological role of LZTS2 using knockout mouse models, 2) examining LZTS2 expression in human prostate cancers, and 3) investigating the dysregulation of Wnt/??-catenin signaling by LZTS2 in prostate tumorigenesis. The above specific aims address the significance of LZTS2 in tumorigenesis and identify the novel mechanisms for dysregulation of Wnt/??-catenin signaling in tumorigenesis. Insights into new diagnostic markers, therapeutic targets and approaches for prostate cancer and other tumors are expected.

Public Health Relevance

Using different experimental approaches, we identified a novel ?-catenin interacting protein, LZTS2 (leucine zipper, putative tumor suppressor 2). In this RO1 application, we propose a series of experiments to further investigate the biological role of LZTS2 in tumorigenesis and in the regulation of the Wnt/??-catenin signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151623-03
Application #
8512670
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
2011-09-13
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$315,839
Indirect Cost
$120,789
Name
Stanford University
Department
Urology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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He, Yongfeng; Hooker, Erika; Yu, Eun-Jeong et al. (2018) Androgen signaling is essential for development of prostate cancer initiated from prostatic basal cells. Oncogene :
Yu, Eun-Jeong; Hooker, Erika; Johnson, Daniel T et al. (2017) LZTS2 and PTEN collaboratively regulate ß-catenin in prostatic tumorigenesis. PLoS One 12:e0174357
Johnson, Daniel T; Hooker, Erika; Luong, Richard et al. (2016) Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice. PLoS One 11:e0148851
Lee, S H; Luong, R; Johnson, D T et al. (2016) Androgen signaling is a confounding factor for ?-catenin-mediated prostate tumorigenesis. Oncogene 35:702-14
Lee, Suk Hyung; Johnson, Daniel; Luong, Richard et al. (2015) Crosstalking between androgen and PI3K/AKT signaling pathways in prostate cancer cells. J Biol Chem 290:2759-68
Lee, Suk Hyung; Johnson, Daniel T; Luong, Richard et al. (2015) Wnt/?-Catenin-Responsive Cells in Prostatic Development and Regeneration. Stem Cells 33:3356-67
Johnson, Daniel T; Luong, Richard; Lee, Suk Hyung et al. (2013) Deletion of leucine zipper tumor suppressor 2 (Lzts2) increases susceptibility to tumor development. J Biol Chem 288:3727-38
Lee, Suk Hyung; Zhu, Chunfang; Peng, Yue et al. (2013) Identification of a novel role of ZMIZ2 protein in regulating the activity of the Wnt/?-catenin signaling pathway. J Biol Chem 288:35913-24

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