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<p>Lung cancer currently holds the highest global incidence and mortality rates among malignant tumors, with lung adenocarcinoma being the most prevalent and deadly subtype. Chemotherapy and targeted therapy remain the standard treatments for lung adenocarcinoma, but tumor resistance continues to be a significant clinical challenge. In this study, we identified that the long non-coding RNA actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1), which is highly expressed in lung adenocarcinoma, regulates RNA alternative splicing by recruiting splicing factors such as serine and arginine rich splicing factor 1 and 3 (SRSF1 and SRSF3), promoting their liquid-liquid phase separation. Among the affected splicing events, the exon 7 skipping of the key regulatory gene AXIN2, involved in the Wnt/β-catenin signaling pathway, is most notably regulated by AFAP1-AS1, resulting in the translation of a truncated AXIN2 isoform (AXIN2-S). This isoform facilitates the accumulation of β-catenin in the nucleus and the persistent activation of Wnt/β-catenin signaling pathway, ultimately contributing to drug resistance in lung adenocarcinoma. Our work uncovers a novel function of AFAP1-AS1 in regulating RNA alternative splicing through the modulation of splicing factors phase separation. This mechanism highlights an unrecognized pathway by which AFAP1-AS1 promotes drug resistance in lung adenocarcinoma, suggesting that AFAP1-AS1 and its regulated splicing events may serve as potential biomarkers or therapeutic targets for the treatment of lung adenocarcinoma.</p> Graphical Abstract <p>Mechanistic model illustrating role of AFAP1-AS1 regulated AXIN2 alternative splicing in drug resistance in lung adenocarcinoma. (Left) In normal cells, AXIN2 is produced through a conventional splicing pattern, resulting in the AXIN2-L isoform, which prevents the nuclear accumulation of β-catenin by forming the β-catenin destruction complex, thereby inhibiting the activation of the Wnt/β-catenin pathway. (Right) In lung adenocarcinoma cells, high expression of AFAP1-AS1 promotes aberrant splicing of AXIN2 pre-mRNA by binding to and enhancing the phase separation of SRSF1 and SRSF3, leading to the generation of the AXIN2-S isoform. This activates the Wnt/β-catenin pathway, driving drug resistance in lung adenocarcinoma.</p> <p></p>

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Long non-coding RNA AFAP1-AS1 promotes alternative splicing of AXIN2 by facilitating SRSFs phase separation to induce drug resistance in lung adenocarcinoma

  • 期刊论文

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  • 发表日期：

    2025年11月20日

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  • Jiawei Ouyang,
  • Yijie Zhang,
  • Xiangchan Hou,
  • Fang Xiong,
  • Lei Shi,
  • Yu Zhong,
  • Liting Yang,
  • Can Guo,
  • Zhaoyang Zeng,
  • Qijia Yan,
  • Pan Chen,
  • Wei Xiong

摘要

Lung cancer currently holds the highest global incidence and mortality rates among malignant tumors, with lung adenocarcinoma being the most prevalent and deadly subtype. Chemotherapy and targeted therapy remain the standard treatments for lung adenocarcinoma, but tumor resistance continues to be a significant clinical challenge. In this study, we identified that the long non-coding RNA actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1), which is highly expressed in lung adenocarcinoma, regulates RNA alternative splicing by recruiting splicing factors such as serine and arginine rich splicing factor 1 and 3 (SRSF1 and SRSF3), promoting their liquid-liquid phase separation. Among the affected splicing events, the exon 7 skipping of the key regulatory gene AXIN2, involved in the Wnt/β-catenin signaling pathway, is most notably regulated by AFAP1-AS1, resulting in the translation of a truncated AXIN2 isoform (AXIN2-S). This isoform facilitates the accumulation of β-catenin in the nucleus and the persistent activation of Wnt/β-catenin signaling pathway, ultimately contributing to drug resistance in lung adenocarcinoma. Our work uncovers a novel function of AFAP1-AS1 in regulating RNA alternative splicing through the modulation of splicing factors phase separation. This mechanism highlights an unrecognized pathway by which AFAP1-AS1 promotes drug resistance in lung adenocarcinoma, suggesting that AFAP1-AS1 and its regulated splicing events may serve as potential biomarkers or therapeutic targets for the treatment of lung adenocarcinoma.

Graphical Abstract

Mechanistic model illustrating role of AFAP1-AS1 regulated AXIN2 alternative splicing in drug resistance in lung adenocarcinoma. (Left) In normal cells, AXIN2 is produced through a conventional splicing pattern, resulting in the AXIN2-L isoform, which prevents the nuclear accumulation of β-catenin by forming the β-catenin destruction complex, thereby inhibiting the activation of the Wnt/β-catenin pathway. (Right) In lung adenocarcinoma cells, high expression of AFAP1-AS1 promotes aberrant splicing of AXIN2 pre-mRNA by binding to and enhancing the phase separation of SRSF1 and SRSF3, leading to the generation of the AXIN2-S isoform. This activates the Wnt/β-catenin pathway, driving drug resistance in lung adenocarcinoma.