Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells
Yazarlar (1)
Prof. Dr. Ercan ÇAÇAN
Tokat Gaziosmanpaşa Üniversitesi, Türkiye
| Makale Türü | Özgün Makale |
| Makale Alt Türü | SSCI, AHCI, SCI, SCI-Exp dergilerinde yayınlanan tam makale |
| Dergi Adı | Cell Biology International |
| Dergi ISSN | 1065-6995 Wos Dergi Scopus Dergi |
| Dergi Tarandığı Indeksler | SCI-Expanded |
| Dergi Grubu | Q4 |
| Makale Dili | İngilizce |
| Basım Tarihi | 03-2017 |
| Cilt No | 41 |
| Sayı | 3 |
| Sayfalar | 328 / 339 |
| DOI Numarası | 10.1002/cbin.10729 |
| Makale Linki | http://dx.doi.org/10.1002/cbin.10729 |
| Özet |
| The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells. |
| Anahtar Kelimeler |
| chemoresistance | co-stimulatory molecules | epigenetics | immune suppression | ovarian cancer |
BM Sürdürülebilir Kalkınma Amaçları
| Atıf Sayıları | |
| WoS | 30 |
| SCOPUS | 29 |
| Google Scholar | 40 |