Dehydropeptidase 1 promotes metastasis through regulation of E-cadherin expression in colon cancer

// Sang Yoon Park 1, 8 , Seon-Jin Lee 1, 2 , Hee Jun Cho 1 , Tae Woo Kim 1, 2 , Jong-Tae Kim 1 , Jae Wha Kim 3 , Chul-Ho Lee 4 , Bo-Yeon Kim 5 , Young Il Yeom 6 , Jong-Seok Lim 7 , Younghee Lee 8 , Hee Gu Lee 1, 2 1 Genome Structure Research Center, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea 2 Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Korea 3 Biomedical Translational Research Center, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea 4 Animal Resource Center, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea 5 World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Korea 6 Department of Functional Genomics, Korea Research Institute of Biosceience and Biotechnology, Daejeon, Korea 7 Department of Biological Sciences, and The Research Center for Women’s Diseases, Sookmyung Women’s University, Seoul, Korea 8 Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Korea Correspondence to: Hee Gu Lee, e-mail: hglee@kribb.re.kr Younghee Lee, e-mail: yhl4177@chungbuk.ac.kr Keywords: colon cancer, invasion, metastasis, E-cadherin, dehydropeptidase 1 Received: October 20, 2015 Accepted: January 19, 2016 Published: January 27, 2016 ABSTRACT Dehydropeptidase 1 (DPEP1) is a zinc-dependent metalloproteinase that is expressed aberrantly in several cancers. The role of DPEP1 in cancer remain controversial. In this study, we demonstrate that DPEP1 functions as a positive regulator for colon cancer cell metastasis. The expression of DPEP1 mRNA and proteins were upregulated in colon cancer tissues compared to normal mucosa. Gain-of-function and loss-of-function approaches were used to examine the malignant phenotype of DPEP1-expressing or DPEP1-depleted cells. DPEP1 expression caused a significant increase in colon cancer cell adhesion and invasion in vitro , and metastasis in vivo . In contrast, DPEP1 depletion induced opposite effects. Furthermore, cilastatin, a DPEP1 inhibitor, suppressed the invasion and metastasis of DPEP1-expressing cells. DPEP1 inhibited the leukotriene D4 signaling pathway and increased the expression of E-cadherin. We also show that DPEP1 mediates TGF-β-induced EMT. TGF-β transcriptionally repressed DPEP1 expression. TGF-β treatment decreased E-cadherin expression and promoted cell invasion in DPEP1-expressing colon cancer cell lines, whereas it did not affect these parameters in DPEP1-depleted cell lines. These results suggest that DPEP1 promotes cancer metastasis by regulating E-cadherin plasticity and that it might be a potential therapeutic target for preventing the progression of colon cancer.