Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo signaling pathway

Jie Liu; Juan Li; Pingping Li; Yaochun Wang; Zheyong Liang; Yina Jiang; Jing Li; Chen Feng; Ruiqi Wang; He Chen; Can Zhou; Jianmin Zhang; Jin Yang; Peijun Liu

doi:10.1038/srep42125

Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo signaling pathway

Sci Rep. 2017 Feb 7:7:42125. doi: 10.1038/srep42125.

Authors

Jie Liu^{1

2}, Juan Li^{1

2}, Pingping Li^{1

2}, Yaochun Wang^{1

2}, Zheyong Liang^{1

2}, Yina Jiang³, Jing Li^{1

2}, Chen Feng⁴, Ruiqi Wang^{1

2}, He Chen^{1

2}, Can Zhou⁵, Jianmin Zhang⁶, Jin Yang⁷, Peijun Liu^{1

2}

Affiliations

¹ Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
² Key Laboratory for Tumor Precision Medicine of Shaanxi Provincer, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
³ Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
⁴ Department of Oncology, the Shaanxi Provincial Corps' Hospital, Xi'an, Shaanxi, China.
⁵ Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
⁶ Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA.
⁷ Department of Medical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract

Discs Large Homolog 5 (DLG5) plays an important role in the maintenance of epithelial cell polarity. Recent research showed that DLG5 is decreased in Yes-associated protein (YAP)-overexpressing cells. However, the exact relationship between DLG5 and YAP is not clear. In this study, we showed that loss of DLG5 promoted breast cancer cell proliferation by inhibiting the Hippo signaling pathway and increasing nuclear YAP expression. Furthermore, depletion of DLG5 induced epithelial-mesenchymal transition (EMT) and disrupted epithelial cell polarity, which was associated with altered expression of Scribble, ZO1, E-cadherin and N-cadherin and their mislocalization. Interestingly, we first reported that loss of DLG5 inhibited the interaction of Mst1 and Lats1 with Scribble, which was crucial for YAP activation and the transcription of TEA domain (TEAD) family members. In summary, loss of DLG5 expression promoted breast cancer malignancy by inactivating the Hippo signaling pathway and increasing nuclear YAP.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Antigens, CD / genetics
Antigens, CD / metabolism
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cadherins / genetics
Cadherins / metabolism
Carcinogenesis / genetics*
Carcinogenesis / metabolism
Carcinogenesis / pathology
Cell Line, Tumor
Cell Polarity
Cell Proliferation
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic*
Hepatocyte Growth Factor / genetics
Hepatocyte Growth Factor / metabolism
Hippo Signaling Pathway
Humans
MCF-7 Cells
Membrane Proteins / deficiency
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice, Nude
Neoplasm Staging
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phosphoproteins / genetics*
Phosphoproteins / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Signal Transduction
TEA Domain Transcription Factors
Transcription Factors / genetics
Transcription Factors / metabolism
Transplantation, Heterologous
Tumor Suppressor Proteins / deficiency
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism
YAP-Signaling Proteins
Zonula Occludens-1 Protein / genetics
Zonula Occludens-1 Protein / metabolism

Substances

Adaptor Proteins, Signal Transducing
Antigens, CD
CDH1 protein, human
CDH2 protein, human
Cadherins
DLG5 protein, human
DNA-Binding Proteins
Membrane Proteins
Nuclear Proteins
Phosphoproteins
Proto-Oncogene Proteins
SCRIB protein, human
TEA Domain Transcription Factors
TEAD1 protein, human
TJP1 protein, human
Transcription Factors
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
Zonula Occludens-1 Protein
macrophage stimulating protein
Hepatocyte Growth Factor
LATS1 protein, human
Protein Serine-Threonine Kinases