FOXA1 Regulation Turns Benzamide HDACi Treatment Effect-Specific in BC, Promoting NIS Gene-Mediated Targeted Radioiodine Therapy
| Autor: | Girish Salve, Abhijit De, Madhura Kelkar, Maitreyi Rathod, Snehal K. Valvi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Sodium-iodide symporter Cancer Research benzamide lcsh:RC254-282 03 medical and health sciences chemistry.chemical_compound breast cancer 0302 clinical medicine Breast cancer HDAC inhibitor sodium iodide symporter Gene expression medicine Pharmacology (medical) Benzamide Thyroid cancer transcriptional factor health care economics and organizations business.industry radio-iodine therapy FOXA1 Cancer lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Cancer research Molecular Medicine Original Article Histone deacetylase FOXA1 business |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 19, Iss, Pp 93-104 (2020) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| DOI: | 10.1016/j.omto.2020.08.015 |
| Popis: | Human sodium iodide symporter (NIS) gene mediated radio-ablation is a successful procedure in thyroid cancer clinics. In recent years, natural expression of NIS is reported in breast cancer (BC) cases but is yet to make its mark as a therapeutic procedure in BC clinics. A pre-exposure to histone deacetylase (HDAC) inhibitors to amplify endogenous NIS expression was attempted, but achieving cancer tissue-specific enhancement of NIS in patients is an important challenge to win. Here, for the first time, we show that a benzamide class of HDACi (bHDACi) can significantly induce NIS gene expression and function (p < 0.05) in BC cells with minimal off-target effects. Transcription factor (TF) profiler and promoter binding array reveals 22 TFs differentially activated by CI-994, of which FOXA1 is identified as a unique and positive regulator of NIS. Clonogenic assay shows reduced survival with bHDACi + 131I combination treatment. Further, AR-42 and MS-275 treatment shows enhanced NIS expression in an orthotopic breast tumor model. Combining bHDACi with 1 mCi 131I shows 40% drop in signal (p < 0.05), indicating enhanced radio-ablation effect. Cerenkov imaging revealed higher accumulation of 131I in MS-275-treated tumors. Thus, bHDACi-mediated selective enhancement ensuring minimal off-target effect is a step further toward using NIS as a therapeutic target for BC. Graphical Abstract In this study, De and colleagues for the first time showed breast cancer tissue-specific transcriptional modulation of the hNIS gene, which can be achieved by using a benzamide class of HDAC inhibitors. Understanding the molecular basis of such cancer tissue-specific regulation may promote targeted radioiodine therapy application in BC patients with higher NIS expression. |
| Databáze: | OpenAIRE |
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