E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα.
All-trans retinoic acid (ATRA) is a widely used differentiation drug that can effectively induce osteogenic differentiation of osteosarcoma cells, but the underlying mechanism remains elusive, which limits the clinical application for ATRA in osteosarcoma patients. In this study, we identified E2F1 as a novel regulator involved in ATRA-induced osteogenic differentiation of osteosarcoma cells. We observed that osteosarcoma cells are coupled with individual differences in the expression levels of E2F1 in patients, and E2F1 impairs ATRA-induced differentiation of osteosarcoma cells. Moreover, remarkable anti-proliferative and differentiation-inducing effects of ATRA treatment are only observed in E2F1 low to negative expressed primary osteosarcoma cultures. These results strongly suggested that E2F1 may serve as a potent indicator for the effectiveness of ATRA treatment in osteosarcoma. Interestingly, E2F1 is found to downregulate retinoic acid receptor α (RARα), a key factor determines the effectiveness of ATRA. E2F1 specifically binds to RARα and promotes its ubiquitination-mediated degradation; as a consequence, RARα-mediated differentiation is inhibited in osteosarcoma. Therefore, our studies present E2F1 as a potent biomarker, as well as a therapeutic target for ATRA-based differentiation therapeutics, and raise the hope of using differentiation-based approaches for osteosarcoma patients.
['Zhang|Lei|L|', 'Zhou|Qian|Q|', 'Zhang|Ning|N|', 'Li|Weixu|W|', 'Ying|Meidan|M|', 'Ding|Wanjing|W|', 'Yang|Bo|B|', 'He|Qiaojun|Q|']
D000970:Antineoplastic Agents D014408:Biomarkers, Tumor D045744:Cell Line, Tumor D050687:E2F1 Transcription Factor D006801:Humans D010012:Osteogenesis D012516:Osteosarcoma D059748:Proteolysis D018168:Receptors, Retinoic Acid D000072482:Retinoic Acid Receptor alpha D014212:Tretinoin D054875:Ubiquitination
E2F1 osteogenic differentiation osteosarcoma RARα all-trans retinoic acid ATRA