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

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.

Expression of miRNA‐26b‐5p and its target TRPS1 is associated with radiation exposure in post‐Chernobyl breast cancer

“…In sporadic breast cancer, an upregulated TRPS1 expression was previously reported which is in line with our findings in the sporadic subset of control cases . In sporadic breast cancer TRPS1 is linked to the stimulation of cell proliferation and angiogenesis and the promotion of cell cycle progression . Furthermore, TRPS1 overexpression was proposed as a prognostic marker in early stage breast cancer due to an association with improved overall survival and disease‐free survival in these tumors .…”

“…34 In sporadic breast cancer TRPS1 is linked to the stimulation of cell proliferation and angiogenesis and the promotion of cell cycle progression. 7,10,12 Furthermore, TRPS1 overexpression was proposed as a prognostic marker in early stage breast cancer due to an association with improved overall survival and disease-free survival in these tumors. 35 Moreover, TRPS1 expression was found to correlate with ER, Figure 3.…”

“…Either mutation or deletion of this gene causes a disease called trichorhinophalangeal syndrome. Previous studies have shown that TRPS1 is expressed in several human malignant tumors and implied an important function in tumor growth, cell cycle, angiogenesis, apoptosis, cell proliferation, migration and metastasis …”

“…Previous studies have shown that TRPS1 is expressed in several human malignant tumors and implied an important function in tumor growth, cell cycle, angiogenesis, apoptosis, cell proliferation, migration and metastasis. [7][8][9][10][11][12][13] In this study, we were able to identify for the first time one miRNA and one of its target proteins to be significantly associated with radiation-associated breast cancer.…”

Two Membrane-Anchored Aspartic Proteases Contribute to Pollen and Ovule Development

“…Aspartic proteases have been widely studied in animals, including b-secretase, pepsin, cathepsin D, etc. (Ingram, 1951;Vassar et al, 1999;Bach et al, 2015). However, research on plant aspartic proteases remains limited.…”