Oncotarget

Research Papers:

Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells

Anne-Sophie Bach, Danielle Derocq, Valérie Laurent-Matha, Philippe Montcourrier, Salwa Sebti, Béatrice Orsetti, Charles Theillet, Céline Gongora, Sophie Pattingre, Eva Ibing, Pascal Roger, Laetitia K Linares, Thomas Reinheckel, Guillaume Meurice, Frank J. Kaiser, Christian Gespach and Emmanuelle Liaudet-Coopman _

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Oncotarget. 2015; 6:28084-28103. https://doi.org/10.18632/oncotarget.4394

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Abstract

Anne-Sophie Bach1,2,3,4, Danielle Derocq1,2,3,4, Valérie Laurent-Matha1,2,3,4, Philippe Montcourrier1,2,3,4, Salwa Sebti1,2,3,4, Béatrice Orsetti1,2,3,4, Charles Theillet1,2,3,4, Céline Gongora1,2,3,4, Sophie Pattingre1,2,3,4, Eva Ibing5, Pascal Roger6, Laetitia K. Linares1,2,3,4, Thomas Reinheckel7, Guillaume Meurice8, Frank J. Kaiser5, Christian Gespach9, Emmanuelle Liaudet-Coopman1,2,3,4

1IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

2INSERM U1194, Montpellier, France

3Université de Montpellier, Montpellier, France

4Institut Régional du Cancer de Montpellier, Montpellier, France

5Universität zu Lübeck, Lübeck, Germany

6Department of Pathology, CHU Nimes, Nimes, France

7Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany

8Functional Genomic Plateform, Institut Gustave Roussy, Villejuif, France

9INSERM U938, Molecular and Clinical Oncology, Paris 6 University Pierre et Marie Curie, Hôpital Saint-Antoine, Paris, France

Correspondence to:

Emmanuelle Liaudet-Coopman, e-mail: emmanuelle.liaudet-coopman@inserm.fr

Keywords: GATA-factor, BAT3, PTHrP promoter, yeast-two hybrid, confocal microscopy

Received: April 22, 2015     Accepted: June 15, 2015     Published: June 27, 2015

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 ERα-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.


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