Anticancer agent FTY720 upregulates cell cycle regulator BTG2 via the SET/TAF-Iβ -PP2A-SMAD3 signaling pathway and induces G2/M arrest in leukemia

BACKGROUND: FTY720-mediated disruption of the SET/TAF-Iβ–PP2A complex induces distinct transcriptional changes, highlighting BTG2 as a consistently upregulated target across leukemia models. Integrated analyses reveal that FTY720 suppresses ERK phosphorylation, stabilizes SMAD3, and promotes BTG2 transcription independently of p53 status. These events culminate in G2/M cell-cycle arrest and reflect a potential SET/TAF-Iβ–PP2A–SMAD3–BTG2 signaling pathway. Our findings suggest BTG2 as both a mechanistic effector and a potential prognostic biomarker in myeloid leukemia. OBJECTIVE: This study aims to define the transcriptional consequences of FTY720-mediated disruption of the SET/TAF-Iβ–PP2A complex and to elucidate the molecular mechanism by which FTY720 induces BTG2 expression and antileukemic effects. METHODS: We performed transcriptome analyses of FTY720-treated THP-1 cells and SET/TAF-Iβ-depleted U2OS cells to identify commonly regulated genes and enriched signaling pathways. RT-qPCR, western blotting, co-immunoprecipitation, and ChIP-qPCR were conducted to validate BTG2 induction and investigate the SET/TAF-Iβ–PP2A–SMAD3 regulatory pathway. Cell-cycle effects were evaluated by assessing cyclin B1 and Cdc25C abundance and by performing cell-cycle profiling following FTY720 treatment. RESULTS: Transcriptome analysis revealed that FTY720 treatment and SET/TAF-Iβ depletion commonly upregulated BTG2, which showed the strongest induction among shared targets. FTY720 stabilized SMAD3 through ERK dephosphorylation and enhanced SMAD3 binding to the BTG2 promoter, leading to increased BTG2 transcription. Functionally, FTY720 reduced cyclin B1 and Cdc25C levels and induced G2/M arrest, consistent with BTG2-mediated cell-cycle regulation. CONCLUSION: These findings suggest that BTG2 may function as a downstream effector of FTY720-mediated SET/TAF-Iβ inhibition and indicate that a SMAD3-dependent mechanism could contribute to G2/M arrest in leukemia.