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Long non-coding RNA STMN1P2 promotes breast cancer doxorubicin resistance by inhibiting pyroptosis through the hnRNPU-EZH2-TARF6-MALT1-caspase-1 pathway

Abstract

Chemotherapeutic resistance is a significant issue in the treatment of breast cancer, which is related to pyroptosis inhibition. Increasing evidence suggests that long non-coding RNAs (lncRNAs) contribute to tumorigenesis and drug resistance. In this study we investigated the role of the lncRNA STMN1P2 in doxorubicin resistance in breast cancer, as well as its correlation with pyroptosis inhibition. Our results showed that the expression levels of lncRNA STMN1P2 were significantly elevated in doxorubicin-resistant breast cancer tissues and cells. We demonstrated that knockdown of STMN1P2 reduced doxorubicin resistance in breast cancer cells; overexpression of STMN1P2 inhibited doxorubicin-induced pyroptosis by reducing the expression of NLRP3, ASC, caspase-1 and GSDMD. Furthermore, STMN1P2 directly bound to and positively regulated heterogeneous nuclear ribonucleoprotein U (hnRNPU), and knockdown of hnRNPU reversed the inhibitory effect of STMN1P2 on pyroptosis and its ability to promote chemoresistance. In doxorubicin-resistant cells, hnRNPU directly bound to enhancer of zeste homologue 2 (EZH2), and STMN1P2 enhanced hnRNPU recruitment of EZH2 and increased EZH2 protein stability. EZH2 acted as a transcription factor to inactivate TNF receptor-associated factor 6 (TRAF6), thereby repressing the binding of TRAF6 with MALT1 and caspase-1, attenuating the canonical pathways of pyroptosis. In MCF7/DOX cells xenograft nude mouse model, we demonstrated that knockdown of STMN1P2 significantly enhanced the suppression of doxorubicin on the tumour growth. This study provides new clues and approaches for the prevention and treatment of breast cancer chemoresistance.

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Fig. 1: STMN1P2 promotes doxorubicin resistance in breast cancer.
Fig. 2: STMN1P2 serves as a suppressor of doxorubicin-induced pyroptosis.
Fig. 3: STMN1P2 interacts with hnRNPU to regulate pyroptosis and doxorubicin resistance.
Fig. 4: STMN1P2 enhances the stability of the hnRNPU binding protein EZH2.
Fig. 5: STMN1P2 inhibits breast cancer pyroptosis through enhancing the ability of hnRNPU to recruit EZH2.
Fig. 6: EZH2 inactivates TRAF6-MALT1 signalling.
Fig. 7: STMN1P2 promotes doxorubicin resistance through inhibition of pyroptosis in vivo.
Fig. 8: Schematic diagram of the mechanism by which STMN1P2 inhibits pyroptosis to promote doxorubicin resistance in breast cancer.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81874121, 81372849, 82173309); Natural Science Foundation of Shanghai (16ZR1403300).

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PZ, YBS and ZLW designed the research and supervised the work. YPJ, BJX and XFZ performed the experiments, analysed data and wrote the paper. LW provided organoid samples. CFW and XW provided the clinical samples. LYL, SYC and PZ collected samples and performed analysis. XLZ and LL were involved in assisting with experiments. All authors read and approved the final manuscript.

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Correspondence to Zheng-lin Wang, Yang-bai Sun or Ping Zhou.

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Jin, Yp., Xu, Bj., Zhang, Xf. et al. Long non-coding RNA STMN1P2 promotes breast cancer doxorubicin resistance by inhibiting pyroptosis through the hnRNPU-EZH2-TARF6-MALT1-caspase-1 pathway. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01653-0

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