E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

Xue Wang; Baijun Dong; Kai Zhang; Zhongzhong Ji; Chaping Cheng; Huifang Zhao; Yaru Sheng; Xiaoxia Li; Liancheng Fan; Wei Xue; Wei-Qiang Gao; Helen He Zhu

doi:10.1371/journal.pgen.1007609

E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

PLoS Genet. 2018 Aug 17;14(8):e1007609. doi: 10.1371/journal.pgen.1007609. eCollection 2018 Aug.

Authors

Xue Wang^{1

2}, Baijun Dong³, Kai Zhang², Zhongzhong Ji², Chaping Cheng², Huifang Zhao², Yaru Sheng², Xiaoxia Li², Liancheng Fan³, Wei Xue³, Wei-Qiang Gao^{1

2}, Helen He Zhu^{1

3}

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cadherins / genetics
Cadherins / physiology*
Carcinogenesis
Cell Division
Cell Line
Cell Polarity*
Cell Proliferation
Disease Models, Animal
Epithelium
Gene Deletion
Gene Expression Regulation
Humans
Male
Mice, Knockout
Prostate / cytology*
Prostatic Neoplasms / pathology
Spindle Apparatus / physiology*

Substances

Cadherins
Cdh1 protein, mouse

Grants and funding

The study is supported by funds from the Chinese Ministry of Science and Technology (2017YFA0102900, 2013CB945600), the National Natural Science Foundation of China (NSFC, 81630073 and 81372189), Science and Technology Commission of Shanghai Municipality (16JC1405700), KC Wong foundation, and SJTU-USYD seed funding for Joint Research to W-QG, NSFC (81772743), the State Key Laboratory of Oncogenes and Related Genes (90-16-03), Shanghai Institutions of Higher Learning (The Program for Professor of Special Appointment (Young Eastern Scholar, QD2015002)), School of Medicine, Shanghai Jiao Tong University (Excellent Youth Scholar Initiation Grant 16XJ11003), Ren Ji Hospital (Seed Project RJZZ14-010) to HHZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.