Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor

• Published in: Molecular and cellular biology 2017-03, Vol.37 (5)
• Main Authors: Burton, Liza J., Dougan, Jodi, Jones, Jasmine, Smith, Bethany N., Randle, Diandra, Henderson, Veronica, Odero-Marah, Valerie A.
• Format: Article
• Language: English
• Subjects: Antigens, CD; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cadherins - genetics; Cadherins - metabolism; cathepsin L; Cathepsin L - metabolism; CDP/Cux; Cell Line, Tumor; Cell Movement - drug effects; Cell Nucleus - drug effects; Cell Nucleus - enzymology; Dipeptides - pharmacology; EMT; Epithelial-Mesenchymal Transition - drug effects; Feedback, Physiological - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Homeodomain Proteins - metabolism; Humans; Male; Mesoderm - drug effects; Mesoderm - pathology; Models, Biological; Neoplasm Invasiveness; Nuclear Proteins - metabolism; Promoter Regions, Genetic - genetics; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Protease Inhibitors - pharmacology; Protein Binding - drug effects; Repressor Proteins - metabolism; RNA, Small Interfering - metabolism; Snail; Snail Family Transcription Factors - metabolism; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism; Transcription, Genetic - drug effects; Z-FY-CHO
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00297-16

The epithelial mesenchymal transition (EMT) promotes tumor migration and invasion by downregulating epithelial markers such as E-cadherin and upregulating mesenchymal markers such as vimentin. Cathepsin L (Cat L) is a cysteine protease that can proteolytically activate CCAAT displacement protein/cut homeobox transcription factor (CUX1). We hypothesized that nuclear Cat L may promote EMT via CUX1 and that this could be antagonized with the Cat L-specific inhibitor Z-FY-CHO. Mesenchymal prostate (ARCaP-M and ARCaP-E overexpressing Snail) and breast (MDA-MB-468, MDA-MB-231, and MCF-7 overexpressing Snail) cancer cells expressed lower E-cadherin activity, higher Snail, vimentin, and Cat L activity, and a p110/p90 active CUX1 form, compared to epithelial prostate (ARCaP-E and ARCaP-Neo) and breast (MCF-7 and MCF-7 Neo) cancer cells. There was increased binding of CUX1 to Snail and the E-cadherin promoter in mesenchymal cells compared to epithelial prostate and breast cells. Treatment of mesenchymal cells with the Cat L inhibitor Z-FY-CHO led to nuclear-to-cytoplasmic relocalization of Cat L, decreased binding of CUX1 to Snail and the E-cadherin promoter, reversed EMT, and decreased cell migration/invasion. Overall, our novel data suggest that a positive feedback loop between Snail-nuclear Cat L-CUX1 drives EMT, which can be antagonized by Z-FY-CHO. Therefore, Z-FY-CHO may be an important therapeutic tool to antagonize EMT and cancer progression.