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, Valerie 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, Emmanuelle Liaudet Coopman

Research output: Contribution to journalArticle

13 Scopus citations

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 ERa-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.

Original languageEnglish (US)
Pages (from-to)28084-28103
Number of pages20
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - Jan 1 2015

Keywords

  • BAT3
  • Confocal microscopy
  • GATA-factor
  • PTHrP promoter
  • Yeast-two hybrid

ASJC Scopus subject areas

  • Oncology

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    Bach, A. S., Derocq, D., Matha, V. L., Montcourrier, P., Sebti, S., Orsetti, B., Theillet, C., Gongora, C., Pattingre, S., Ibing, E., Roger, P., Linares, L. K., Reinheckel, T., Meurice, G., Kaiser, F. J., Gespach, C., & Coopman, E. L. (2015). Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells. Oncotarget, 6(29), 28084-28103. https://doi.org/10.18632/oncotarget.4394