LZTS2 and PTEN collaboratively regulate ß-catenin in prostatic tumorigenesis.
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.
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.|Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Eun-Jeong
EJ
Yu
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.|Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Erika
E
Hooker
Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Daniel T
DT
Johnson
Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Mi Kyung
MK
Kwak
Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Kang
K
Zou
Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
Richard
R
Luong
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.|Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Yongfeng
Y
He
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.|Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America.
Zijie
http://orcid.org/0000-0002-6787-6272
Z
Sun
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C569000:LZTS2 protein, mouse; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse