DSG3 Facilitates Cancer Cell Growth and Invasion through the DSG3-Plakoglobin-TCF/LEF-Myc/Cyclin D1/MMP Signaling Pathway

Yin Ju Chen, Li Yu Lee, Yin Ka Chao, Joseph T. Chang, Ya Ching Lu, Hsiao Fang Li, Ching Chi Chiu, Yi Chen Li, Yan Liang Li, Jeng Fong Chiou, Ann Joy Cheng

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Abstract

Desmoglein 3 (DSG3) is a component of the desmosome, which confers strong cell-cell adhesion. Previously, an oncogenic function of DSG3 has been found in head neck cancer (HNC). Here, we investigated how this molecule contributes to the malignant phenotype. Because DSG3 is associated with plakoglobin, we examined whether these phenotypic alterations were mediated through the plakoglobin molecule. Immunoprecipitation and immunofluorescence staining revealed that DSG3 silencing disrupted its interaction with plakoglobin and induced plakoglobin translocation from the cytoplasm to the nucleus. Knockdown of DSG3 significantly increased the interaction of plakoglobin with the transcriptional factor TCF and suppressed the TCF/LEF transcriptional activity. These effects further conferred to reduced expression of the TCF/LEF downstream target genes, including c-myc, cyclin D1, and MMP-7. Functional analyses showed that DSG3 silencing reduced cell growth and arrested cells at G0/G1 phase. Besides, cell migration and invasion abilities were also decreased. These cellular results were confirmed using tumor xenografts in mice, as DSG3 silencing led to the suppressed tumor growth, plakoglobin translocation and reduced expression of TCF/LEF target genes in tumors. Therefore, our study shows that the desmosomal protein DSG3 additionally functions to regulate malignant phenotypes via nuclear signaling. In conclusion, we found that DSG3 functions as an oncogene and facilitates cancer growth and invasion in HNC cells through the DSG3-plakoglobin-TCF/LEF pathway.

Original languageEnglish
Article numbere64088
JournalPLoS One
Volume8
Issue number5
DOIs
Publication statusPublished - May 30 2013

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chen, Y. J., Lee, L. Y., Chao, Y. K., Chang, J. T., Lu, Y. C., Li, H. F., Chiu, C. C., Li, Y. C., Li, Y. L., Chiou, J. F., & Cheng, A. J. (2013). DSG3 Facilitates Cancer Cell Growth and Invasion through the DSG3-Plakoglobin-TCF/LEF-Myc/Cyclin D1/MMP Signaling Pathway. PLoS One, 8(5), [e64088]. https://doi.org/10.1371/journal.pone.0064088