DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression

• Published in: British journal of cancer Vol. 110; no. 5; pp. 1298 - 1306
• Main Authors: Ismail, I A, Kang, H S, Lee, H-J, Kim, J-K, Hong, S-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2014; Nature Publishing Group
• Subjects: 631/67/1347; 631/80/84/2336; 631/80/86; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Cell Line, Tumor; Down-Regulation; Drug Resistance; Epidemiology; Female; Gynecology. Andrology. Obstetrics; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Mammary gland diseases; MCF-7 Cells; Medical sciences; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncology; Promoter Regions, Genetic; Protein Deglycase DJ-1; Transcription Factors - antagonists & inhibitors; Transcription Factors - biosynthesis; Transcription Factors - genetics; Tumors; Up-Regulation; breast cancer cells; epithelial–mesenchymal transition (EMT); DJ-1 (PARK7); invasion; Ras; ID-1; KLF17; Breast disease; Breast cancer; Tumorous infiltration; Id1 gene; Malignant tumor; Metastasis; Cell transformation; Invasion; Mammary gland diseases; epithelial-mesenchymal transition (EMT); Cancerology; C-Onc gene; Epithelial mesenchymal transition; Ras gene; Tumor cell; Protooncogene; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.40

Background: DJ-1 (PARK7) was reported as an oncogene in a Ras-dependent manner. Recent studies have shown that DJ-1 stimulates cell proliferation, cell invasion, and cancer metastasis. However, the molecular mehchanism by which DJ-1 induces cancer cell invasion and metastasis remains unclear. Methods: Breast cancer cells were transfected with DJ-1 siRNA or DJ-1 overexpression to investigate the effect of DJ-1 on KLF17 expression. ID-1 luciferase promoter assay was performed to evaluate DJ-1-dependent KLF17 expression changes. In addition, Epistasis analysis of DJ-1 and KLF17 was performed to evaluate their regulatory interactions. Ras inhibitors were pretreated to determine whether DJ-1 regulates cell invasion in a Ras-dependent manner. Results: In the present study, we found increased DJ-1 expression in highly invasive breast cancer cells as compared with non-metastatic cells. Furthermore, DJ-1 promoted breast cancer cell invasion by downregulating E-cadherin and increasing Snail expression. Interestingly, exogenous DJ-1 overexpression markedly decreased mRNA and protein expression of KLF17, the EMT negative regulator. These data were confirmed by ID-1 promoter activity, which is directly regulated by DJ-1-dependent KLF17 transcription factor. Epistasis analysis showed that KLF17 overexpression overcomes increased cell invasion by DJ-1, suggesting that KLF17 might be one of the downstream signalling molecules of DJ-1. Acceleration of cell invasion by DJ-1 was alleviated by Ras inhibitors, suggesting that DJ-1 cooperates with Ras to increase cell invasion. Conclusion: Altogether, these data suggest for the first time that DJ-1 acts as an EMT-positive regulator in breast cancer cells via regulation of the KLF17/ID-1 pathway.