All-trans retinoic acid induces Thrombospondin-1 expression in acute promyelocytic leukemia cells though down-regulation of its transcription repressor, c-MYC oncoprotein

Thrombospondin-1 (TSP-1) was found to mediate the therapeutic effects of all-trans retinoic acid (ATRA) for leukemia. The aim of the present study was to evaluate the role of c-MYC, a key transcription factor that contributes to the genesis of many human tumors, in TSP-1 induction by ATRA in acute promyelocytic leukemia (APL). ATRA treatment markedly increased TSP-1 level and inhibited c-MYC expression in NB4 APL leukemic cells compared with controls. Promoter assays indicated that c-MYC responsive element is functional relevant to the induction of TSP-1 promoter activity by ATRA. c-MYC recruitment to TSP-1 promoter was dramatically decreased in NB4 cells following ATRA treatment. shRNA-mediated inhibition of c-MYC resulted in a marked up-regulation of endogenous TSP-1 expression. Moreover, transient over-expression of c-MYC totally abolished TSP-1 induction by ATRA in NB4 cells. Collectively, our results indicate that ATRA induces TSP-1 expression in APL cells though down-regulation of its transcription repressor, c-MYC oncoprotein.