靶向 TRIM59 损害 RNA 剪接并促进神经母细胞瘤分化与治疗反应

Clinical outcomes in neuroblastoma (NB) are closely linked to its differentiation status, making the reversal of differentiation arrest a highly promising therapeutic objective. However, the mechanisms that govern neuronal differentiation in NB remain unclear. In this study, we identify TRIM59 as a key regulator of RNA splicing that drives NB differentiation via an SFPQ-dependent mechanism.

To identify and target regulators of differentiation in high-risk NB, we collected 98 clinical NB tumor specimens and then performed RNA sequencing (RNA-seq) analysis. The effects of TRIM59 knockdown on NB differentiation were investigated by immunofluorescence staining, qRT-PCR, western blotting, and IHC staining. The replicate Multivariate Analysis of Transcript Splicing (rMATS) analysis and mass spectrometry was used to assess the role of TRIM59 in RNA splicing and its associated protein, respectively. We developed TRIM59-gRNA adeno-associated virus (AAV) to treat animals bearing NB xenograft tumors. The antitumor activity and survival outcomes of AAV-TRIM59-gRNA in combination with chemotherapy or CAR-T immunotherapy in vivo were further evaluated.

TRIM59-depleted NBs exhibit enhanced neuronal differentiation phenotypes and activation of related signaling pathways, as demonstrated by RNA-seq and functional studies. This effect can be restored by genetically overexpressing the SEMA4F-L isoform, but not SEMA4F-S, mediated by RNA splicing factor SFPQ. Mechanistically, TRIM59 deletion promotes differentiation through SEMA4F-S isoform upregulation, which is mediated by TRIM59 s control of SFPQ nuclear translocation via the PIN1-importin axis and PRMT1-dependent asymmetric dimethylation. Therapeutically, adeno-associated virus (AAV)-delivered TRIM59-targeting gRNA enhance vincristine (VCR) efficacy by enhancing differentiation. Furthermore, TRIM59 depletion potentiates B7-H3 CAR-T efficacy via IRF1-L-mediated immunomodulation. Clinical data corroborates TRIM59 s negative correlation with immunotherapy response.

Together, these findings highlight TRIM59 s new functions in RNA splicing and NB differentiation, suggesting that targeting TRIM59 has the potential to improve the efficacy of both chemotherapy and immunotherapy in high-risk NBs.