Actin cytoskeleton depolymerization increases matrix metalloproteinase gene expression in breast cancer cells by promoting translocation of cysteine-rich protein 2 to the nucleus.
[en] The actin cytoskeleton plays a critical role in cancer cell invasion and metastasis; however, the coordination of its multiple functions remains unclear. Actin dynamics in the cytoplasm control the formation of invadopodia, which are membrane protrusions that facilitate cancer cell invasion by focusing the secretion of extracellular matrix-degrading enzymes, including matrix metalloproteinases (MMPs). In this study, we investigated the nuclear role of cysteine-rich protein 2 (CRP2), a two LIM domain-containing F-actin-binding protein that we previously identified as a cytoskeletal component of invadopodia, in breast cancer cells. We found that F-actin depolymerization stimulates the translocation of CRP2 into the nucleus, resulting in an increase in the transcript levels of pro-invasive and pro-metastatic genes, including several members of the MMP gene family. We demonstrate that in the nucleus, CRP2 interacts with the transcription factor serum response factor (SRF), which is crucial for the expression of MMP-9 and MMP-13. Our data suggest that CRP2 and SRF cooperate to modulate of MMP expression levels. Furthermore, Kaplan-Meier analysis revealed a significant association between high-level expression of SRF and shorter overall survival and distant metastasis-free survival in breast cancer patients with a high CRP2 expression profile. Our findings suggest a model in which CRP2 mediates the coordination of cytoplasmic and nuclear processes driven by actin dynamics, ultimately resulting in the induction of invasive and metastatic behavior in breast cancer cells.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Mgrditchian, Takouhie; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
Brown-Clay, Joshua; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
Hoffmann, Céline; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
Müller, Tanja; Department of Cancer Research, Luxembourg Centre of Neuropathology, Luxembourg Institute of Health, Luxembourg, Luxembourg
Filali, Liza; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
Ockfen, Elena; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
MAO, Xianqing ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) > Medical Education ; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
Moreau, Flora; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
Casellas, Carla Pou; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
MITTELBRONN, Michel ; University of Luxembourg ; Department of Cancer Research, Luxembourg Centre of Neuropathology, Luxembourg Institute of Health, Luxembourg, Luxembourg ; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg ; Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg
Thomas, Clément; Department of Cancer Research, Cytoskeleton and Cancer Progression, Luxembourg Institute of Health, Luxembourg, Luxembourg
External co-authors :
no
Language :
English
Title :
Actin cytoskeleton depolymerization increases matrix metalloproteinase gene expression in breast cancer cells by promoting translocation of cysteine-rich protein 2 to the nucleus.
Joshua Brown-Clay and TM are recipients of Postdoctoral fellowships from Fonds De La Recherche Scientifique, Télévie (Belgium; Télévie 7.4512.16 and 7.4537.19). This work is supported by a research grant from the Fondation Cancer Luxembourg (FC/2016/02) and the National Research Fund (Luxembourg; FNR C16/BM/11297905). TM and CPC are supported by Marian Aldred Awards from Think Pink Lux. EO is recipient of a PhD fellowship from the National Research Fund (FNR PRIDE19/14254520/i2Tron). MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant).Joshua Brown-Clay and TM are recipients of Postdoctoral fellowships from Fonds De La Recherche Scientifique, Télévie (Belgium; Télévie 7.4512.16 and 7.4537.19). This work is supported by a research grant from the Fondation Cancer Luxembourg (FC/2016/02) and the National Research Fund (Luxembourg; FNR C16/BM/11297905). TM and CPC are supported by Marian Aldred Awards from Think Pink Lux. EO is recipient of a PhD fellowship from the National Research Fund (FNR PRIDE19/14254520/i2Tron). MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant).
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