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HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.

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Fig. 1: High expression of HBXIP reduces cisplatin sensitivity in hepatoma.
Fig. 2: HBXIP promotes DNA damage repair and inhibits cisplatin sensitivity.
Fig. 3: HBXIP-mediated upregulation of PARP1 promotes DNA damage repair and enhances cisplatin resistance.
Fig. 4: HBXIP promotes PARP1 promoter activity by coactivating CEBPA.
Fig. 5: HBXIP promotes PARP1 mRNA methylation and RNA stability by upregulating WTAP expression.
Fig. 6: ASA suppresses the HBXIP/ PARP1 axis by reducing HBXIP expression.
Fig. 7: ASA targets the HBXIP/WTAP axis to alleviate cisplatin resistance.

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All relevant data are included in the manuscript and its Supplementary materials file or available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (82072943, China), the National Natural Science Foundation of China (82072929, China).

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Contributions

LHY, WYZ, and XLF contributed to the conceptualization and design of the study. XLF, JQM, SMG, and FYM performed the experiments. XLF drafted the manuscript and analyzed the data. XW, YL, and YXT participated in regular discussions and manuscript revisions. LHY and WYZ provided funding support, supervised the study, and revised the manuscript. All authors participated in data discussions, and proofread the manuscript.

Corresponding authors

Correspondence to Wei-ying Zhang or Li-hong Ye.

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Fu, Xl., Guo, Sm., Ma, Jq. et al. HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01309-5

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