| Added by | mollevi |
|---|---|
| Last modified by | celine.gongora |
| Group name | EquipeCG |
| 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 | A. S. Bach |
| Author | D. Derocq |
| Author | V. Laurent-Matha |
| Author | P. Montcourrier |
| Author | S. Sebti |
| Author | B. Orsetti |
| Author | C. Theillet |
| Author | C. Gongora |
| Author | S. Pattingre |
| Author | E. Ibing |
| Author | P. Roger |
| Author | L. K. Linares |
| Author | T. Reinheckel |
| Author | G. Meurice |
| Author | F. J. Kaiser |
| Author | C. Gespach |
| Author | E. 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 ERalpha-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 |
| Pages | 28084-103 |
| Date | Sep 29 2015 |
| Journal Abbr | Oncotarget |
| DOI | 10.18632/oncotarget.4394 |
| ISSN | 1949-2553 (Electronic) 1949-2553 (Linking) |
| Tags | chemores, original, phd |
| Date Added | 2018/07/20 - 10:05:58 |
| Date Modified | 2019/10/24 - 15:41:50 |
| Notes and Attachments | (Note) (Note) 26183398 (Attachment) |
Institut de Recherche en Cancérologie de
