| Added by | liaudet-coopman |
|---|---|
| Last modified by | tchardes |
| Group name | EquipeELC |
| Item Type | Journal Article |
| Title | Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells |
| Creator | Bach et al. |
| Author | Anne-Sophie Bach |
| Author | Danielle Derocq |
| Author | Valérie Laurent-Matha |
| Author | Philippe Montcourrier |
| Author | Salwa Sebti |
| Author | Béatrice Orsetti |
| Author | Charles Theillet |
| Author | Céline Gongora |
| Author | Sophie Pattingre |
| Author | Eva Ibing |
| Author | Pascal Roger |
| Author | Laetitia K. Linares |
| Author | Thomas Reinheckel |
| Author | Guillaume Meurice |
| Author | Frank J. Kaiser |
| Author | Christian Gespach |
| Author | Emmanuelle Liaudet-Coopman |
| Abstract | The lysosomal protease cathepsin D (Cath-D) is overproduced in breast cancer cells (BCC) and supports tumor growth and metastasis formation. Here, we describe the mechanism whereby Cath-D is accumulated in the nucleus of ER?-positive (ER+) BCC. We identified TRPS1 (tricho-rhino-phalangeal-syndrome 1), a repressor of GATA-mediated transcription, and BAT3 (Scythe/BAG6), a nucleo-cytoplasmic shuttling chaperone protein, as new Cath-D-interacting nuclear proteins. Cath-D binds to BAT3 in ER+ BCC and they partially co-localize at the surface of lysosomes and in the nucleus. BAT3 silencing inhibits Cath-D accumulation in the nucleus, indicating that Cath-D nuclear targeting is controlled by BAT3. Fully mature Cath-D also binds to full-length TRPS1 and they co-localize in the nucleus of ER+ BCC where they are associated with chromatin. Using the LexA-VP16 fusion co-activator reporter assay, we then show that Cath-D acts as a transcriptional repressor, independently of its catalytic activity. Moreover, microarray analysis of BCC in which Cath-D and/or TRPS1 expression were silenced indicated that Cath-D enhances TRPS1-mediated repression of several TRPS1-regulated genes implicated in carcinogenesis, including PTHrP, a canonical TRPS1 gene target. In addition, co-silencing of TRPS1 and Cath-D in BCC affects the transcription of cell cycle, proliferation and transformation genes, and impairs cell cycle progression and soft agar colony formation. These findings indicate that Cath-D acts as a nuclear transcriptional cofactor of TRPS1 to regulate ER+ BCC proliferation and transformation in a non-proteolytic manner. |
| Publication | Oncotarget |
| Volume | 6 |
| Issue | 29 |
| Pages | 28084-28103 |
| Date | Sep 29, 2015 |
| Journal Abbr | Oncotarget |
| Language | eng |
| DOI | 10.18632/oncotarget.4394 |
| ISSN | 1949-2553 |
| Library Catalog | PubMed |
| Extra | PMID: 26183398 PMCID: PMC4695046 |
| Tags | BAT3, Breast Neoplasms, Cathepsin D, Cell Cycle, Cell Nucleus, Cell Proliferation, cnrs, confocal microscopy, DNA-Binding Proteins, first-last-corresponding, GATA-factor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, MCF-7 Cells, Microscopy, Fluorescence, Molecular Chaperones, original, Parathyroid Hormone-Related Protein, Protein Binding, PTHrP promoter, Receptors, Estrogen, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Transcription Factors, Transcription, Genetic, Two-Hybrid System Techniques, yeast-two hybrid |
| Date Added | 2018/09/26 - 14:32:52 |
| Date Modified | 2023/04/06 - 16:49:27 |
Institut de Recherche en Cancérologie de
