title: E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα.
abstract: 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.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Orthopedics; The Second Affiliated Hospital of Zhejiang University; Zhejiang University; Hangzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics; The Second Affiliated Hospital of Zhejiang University; Zhejiang University; Hangzhou, China.
authors.forename: Weixu
authors.initials: W
authors.lastname: Li
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
authors.forename: Meidan
authors.initials: M
authors.lastname: Ying
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
authors.forename: Wanjing
authors.initials: W
authors.lastname: Ding
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D010012:Osteogenesis / Q000187:drug effects*; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin
keywords: ATRA; E2F1; RARα; all-trans retinoic acid; osteogenic differentiation; osteosarcoma