Targeting the nuclear cathepsin L CCAAT displacement protein/cut homeobox transcription factor-epithelial mesenchymal transition pathway in prostate and breast …

LJ Burton, J Dougan, J Jones, BN Smith… - … and cellular biology, 2017 - Taylor & Francis
LJ Burton, J Dougan, J Jones, BN Smith, D Randle, V Henderson, VA Odero-Marah
Molecular and cellular biology, 2017Taylor & Francis
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 …
Abstract
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.
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