LZTS2 and PTEN collaboratively regulate ß-catenin in prostatic tumorigenesis

• Published in: PloS one Vol. 12; no. 3; p. e0174357
• Main Authors: Yu, Eun-Jeong, Hooker, Erika, Johnson, Daniel T, Kwak, Mi Kyung, Zou, Kang, Luong, Richard, He, Yongfeng, Sun, Zijie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.03.2017; Public Library of Science (PLoS)
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Biology and Life Sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Cellular signal transduction; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; Gene Expression Regulation - genetics; Genetic aspects; Genetic Predisposition to Disease; Humans; Male; Medicine and Health Sciences; Mice; Mice, Knockout; Promoter Regions, Genetic - genetics; Prostate cancer; Prostatic Neoplasms - pathology; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Research and Analysis Methods; RNA Interference; RNA, Small Interfering - genetics; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Wnt proteins; Wnt Signaling Pathway - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174357

The leucine zipper tumor suppressor 2 (LZTS2) was identified as a tumor susceptibility gene within the 10q24.3 chromosomal region, and is approximately 15Mb from the PTEN locus. This region containing the both loci is frequently deleted in a variety of human malignancies, including prostate cancer. LZTS2 is a ß-catenin-binding protein and a negative regulator of Wnt signaling. Overexpression of PTEN in prostate cancer cell lines reduces ß-catenin-mediated transcriptional activity. In this study, we examined the collaborative effect of PTEN and LZTS2 using multiple in vitro and in vivo approaches. Co-expression of PTEN and LZTS2 in prostate cancer cells shows stronger repressive effect on ß-catenin mediated transcription. Using a newly generated mouse model, we further assessed the effect of simultaneous deletion of Pten and Lzts2 in the murine prostate. We observed that mice with both Lzts2 and Pten deletion have an earlier onset of prostate carcinomas as well as an accelerated tumor progression compared to mice with Pten or Lzts2 deletion alone. Immunohistochemical analyses show that atypical and tumor cells from compound mice with both Pten and Lzts2 deletion are mainly composed of prostate luminal epithelial cells and possess higher levels of cytoplasmic and nuclear β-catenin. These cells also exhibit a higher proliferative capacity than cells isolated from single deletion mice. These data demonstrate the significance of simultaneous Pten and Lzts2 deletion in oncogenic transformation in prostate cells and implicates a new mechanism for the dysregulation of Wnt/β-catenin signaling in prostate tumorigenesis.