title: All-trans retinoic acid suppresses topoisomerase IIα through the proteasomal pathway.
abstract: Topoisomerase IIα is a nuclear enzyme that alters DNA topology. It is a well-known anticancer target and related to cell differentiation status. All-trans retinoic acid (ATRA), an important active metabolite of vitamin A, is a promising anticancer agent in numerous malignancies. However, there are little data on the effect of retinoids on topoisomerase IIα regulation. In the present study, we investigated the relationship between ATRA and topoisomerase IIα, and the potential mechanisms of ATRA on topoisomerase IIα regulation. In several human carcinoma cell lines, ATRA was shown to suppress topoisomerase IIα protein, but not mRNA expression. ATRA induced the degradation of topoisomerase IIα through the proteasome pathway, but not the lysosome pathway. Ubiquitination was involved in this degradation. Western blot and immunocytochemistry proved that ATRA-induced topoisomerase IIα repression occurred only in the cell nuclei. ATRA not only influenced the cycle procession but also reduced the expression of cyclin D1. Cyclin D1, which is involved in cell differentiation, was regulated by topoisomerase IIα. Similar to cyclin D1, knockdown of topoisomerase IIα resulted in the increased differentiation of the cells, which was in contrast to the overexpression of topoisomerase IIα in the cells. Taken together, these data suggested that ATRA could target topoisomerase IIα and exert potential beneficial effects on cell differentiation.
authors.affiliation: aDepartment of Nutrition and Food Safety, Nanjing Medical University bDepartment of Gynecology of the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Shen
authors.forename: Shilong
authors.initials: S
authors.lastname: Fu
authors.forename: Suping
authors.initials: S
authors.lastname: Han
authors.forename: Qing
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D019938:Cyclin D1; D014212:Tretinoin; D046988:Proteasome Endopeptidase Complex; D004250:DNA Topoisomerases, Type II