Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/20318
Título
HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling.
Autor(es)
Terri, Michela | Sandoval, Pilar | Bontempi, Giulio | Montaldo, Claudia | Tomero-Sanz, Henar | de Turris, Valeria | Trionfetti, Flavia | Pascual-Antón, Lucía | Clares-Pedrero, Irene | Battistelli, Cecilia | Valente, Sergio | Zwergel, Clemens | Mai, Antonello | Rosanò, Laura | del Pozo, Miguel Angel CNIC | Sánchez-Álvarez, Miguel | Cabañas, Carlos | Tripodi, Marco | López-Cabrera, Manuel | Strippoli, Raffaele CNIC
Fecha de publicación
2024-01-23
Cita
J Exp Clin Cancer Res. 2024 Jan 23;43(1):27.
Idioma
Inglés
Tipo de documento
journal article
Resumen
BACKGROUND
Peritoneal metastasis, which accounts for 85% of all epithelial ovarian carcinoma (EOC) metastases, is a multistep process that requires the establishment of adhesive interactions between cancer cells and the peritoneal membrane. Interrelations between EOC and the mesothelial stroma are critical to facilitate the metastatic process. No data is available so far on the impact of histone acetylation/deacetylation, a potentially relevant mechanism governing EOC metastasis, on mesothelial cells (MCs)-mediated adhesion.
METHODS
Static adhesion and peritoneal clearance experiments were performed pretreating mesenchymal-like MCs and platinum-sensitive/resistant EOC cell lines with MS-275-a Histone deacetylase (HDAC)1-3 pharmacological inhibitor currently used in combination trials. Results were acquired by confocal microscopy and were analyzed with an automated Opera software. The role of HDAC1/2 was validated by genetic silencing. The role of α4-, α5-α1 Integrins and Fibronectin-1 was validated using specific monoclonal antibodies. Quantitative proteomic analysis was performed on primary MCs pretreated with MS-275. Decellularized matrices were generated from either MS-275-exposed or untreated cells to study Fibronectin-1 extracellular secretion. The effect of MS-275 on β1 integrin activity was assessed using specific monoclonal antibodies. The role of Talin-1 in MCs/EOC adhesion was analyzed by genetic silencing. Talin-1 ectopic expression was validated as a rescue tool from MS-275-induced phenotype. The in vivo effect of MS-275-induced MC remodeling was validated in a mouse model of peritoneal EOC dissemination.
RESULTS
Treatment of MCs with non-cytotoxic concentrations of MS-275 caused a consistent reduction of EOC adhesion. Proteomic analysis revealed several pathways altered upon MC treatment with MS-275, including ECM deposition/remodeling, adhesion receptors and actin cytoskeleton regulators. HDAC1/2 inhibition hampered actin cytoskeleton polymerization by downregulating actin regulators including Talin-1, impairing β1 integrin activation, and leading to abnormal extracellular secretion and distribution of Fibronectin-1. Talin-1 ectopic expression rescued EOC adhesion to MS-275-treated MCs. In an experimental mouse model of metastatic EOC, MS-275 limited tumor invasion, Fibronectin-1 secretion and the sub-mesothelial accumulation of MC-derived carcinoma-associated fibroblasts.
CONCLUSION
Our study unveils a direct impact of HDAC-1/2 in the regulation of MC/EOC adhesion and highlights the regulation of MC plasticity by epigenetic inhibition as a potential target for therapeutic intervention in EOC peritoneal metastasis.
MESH
Benzamides | Carcinoma, Ovarian Epithelial | Histone Deacetylase 1 | Ovarian Neoplasms | Peritoneal Neoplasms | Histone Deacetylase 2 | Cell Adhesion | Animals | Female | Humans | Mice | Actin Cytoskeleton | Antibodies, Monoclonal | Epithelium | Extracellular Matrix Proteins | Fibronectins | Integrin alpha5 | Integrin beta1 | Proteomics | Pyridines | Talin
Versión en línea
DOI
Aparece en las colecciones
Ficheros en el ítem
![Acceso Abierto Acceso Abierto](/themes/Mirage2/images/openAccess.png)
- Nombre:
- HDAC1_2 control mesothelium_ovarian ...
- Tamaño:
- 7.737Mb
- Formato:
- Descripción:
- Artículo