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Saikosaponin‑D triggers cancer death by targeting the PIM1/c-Myc axis to rewire oncogenic alternative splicing

ABSTRACT: Saikosaponins (SSs, including SSA, SSB, SSC, and SSD), the major bioactive compounds in the traditional medicine Radix Bupleuri (RB), are emerging agents exhibiting anti-tumor efficacy in several cancers. However, the respective anti-tumor efficacy of these agents and mechanisms in cancers such as gastric and prostate cancer remains unclear. In this study, we demonstrated that SSD, among SSs, possessed a significant anti-tumor role in vivo and in vitro. Transcriptome analysis revealed a down-regulation of alternative splicing factors and rewiring of oncogenic alternative splicing events such as CYP1A1, whose transcript-specific ablation with CIRSPR-Cas13 significantly abolished SSD-induced cell growth inhibition. Specifically, we showed that SSD binds to PIM1 and down-regulates its expression, thus restraining PIM1-mediated serine 62 phosphorylation of Myc, which is critical for its transcription activity. This results in decreasing the expression of Myc-governed alternative splicing factors that are responsible for the regulation of oncogenic alternative splicing events. These studies demonstrated the potent anti-tumor efficacy of SSD and exposed a PIM1/Myc pathway that drives the expression of an essential alternative splicing regulatory network that mediates SSD’s anti-tumor role in cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277023 | GEO | 2025/09/04

REPOSITORIES: GEO

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