Hesperetin promotes DOT1L degradation and reduces histone H3K79 methylation to inhibit gastric cancer metastasis |
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| Affiliation: | 1. Quzhou Hospital, Zhejiang University School of Medicine, Quzhou 324000, China;2. Department of Core Facility, Quzhou People''s Hospital, Quzhou 324000, China;3. Zhejiang University School of Medicine, Hangzhou 310058, China;4. Department of Clinical Laboratory, Quzhou People''s Hospital, Quzhou 324000, China;1. Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan ROC;2. Department of Medicine Chest, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan ROC;3. Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, Taipei 11221, Taiwan ROC;4. Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan ROC;5. Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC;6. Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan ROC;7. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC;8. Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC;1. Department of Pharmacognosy and Phytochemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad 380054, Gujarat, India;2. Registered Ph.D. student at Department of Life science, School of Science, Gujarat University, Ahmedabad, Gujarat, India |
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| Abstract: | BackgroundThere have been many researches on the effects of flavonoids on tumor treatment or adjuvant therapy, but there are few studies revealing their epigenetic effect on tumors. Hesperetin is a common citrus flavanone widely distributed among citrus fruits. The role of hesperetin in gastric cancer metastasis is unclear.PurposeTo investigate the effect of hesperetin on gastric cancer metastasis and its underlying mechanism.MethodsWe used cancer cell lines cultured in medium and nude mice implantation as in vitro and in vivo models to investigate the impact of hesperetin treatment on the migration and invasion of gastric cancer cells. The molecular biological experiments such as transwell assay, western blotting, qPCR, ChIP-qPCR, immunostaining and transfection were conducted to explore the molecular mechanisms.ResultsWe found that hesperetin obviously reduced the protein abundance of DOT1L and the methylation of histone H3K79 in a variety of cells. In gastric cancer cells, the treatment of hesperetin decreased cell migration and invasion and the expression of genes closely related to the metastatic capability. Mechanistically, hesperetin affected the stability of DOT1L protein by regulating the activity of CBP.ConclusionThese findings highlight the epigenetic effect of hesperetin and provide a new perspective to understand the tumor suppressive effect of flavonoids. |
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