FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells
| العنوان: | FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells |
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| المؤلفون: | Naotaka Hayasaka, Yohei Arihara, Hajime Nakamura, Shohei Kikuchi, Yusuke Sugama, Kohichi Takada, Masayoshi Kobune, Masahiro Hirakawa, Koji Miyanishi, Makoto Usami, Michihiro Ono, Yuuki Ikeda, Makoto Yoshida, Junji Kato |
| المصدر: | Pancreas. 49:135-142 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cell cycle checkpoint, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Histone Deacetylases, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cell Line, Tumor, Pancreatic cancer, Internal Medicine, medicine, Forkhead Box, Humans, Transcription factor, Cell Proliferation, Regulation of gene expression, Chemotherapy, Hepatology, business.industry, Gene Expression Profiling, Forkhead Box Protein O3, Cancer, Drug Synergism, medicine.disease, G1 Phase Cell Cycle Checkpoints, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Pancreatic Neoplasms, Cell culture, 030220 oncology & carcinogenesis, Cancer research, 030211 gastroenterology & hepatology, business, Oligopeptides, Proteasome Inhibitors, Proto-Oncogene Proteins c-akt, Signal Transduction |
| الوصف: | Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects.We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib.We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib.Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC. |
| تدمد: | 1536-4828 0885-3177 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0c3889429581490e7a33338988e6aca0 https://doi.org/10.1097/mpa.0000000000001462 |
| رقم الأكسشن: | edsair.doi.dedup.....0c3889429581490e7a33338988e6aca0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15364828 08853177 |
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