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STAT3-mediated transactivation of NOVA2 promotes lung adenocarcinoma metastasis by splicing SMAD4

Oncogene (2026)Cite this article

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Abstract

Metastasis remains the primary cause of mortality in lung adenocarcinoma (LUAD) patients. However, the molecular mechanisms underlying LUAD cell metastasis are only partially elucidated. Here, by performing integrated bioinformatic analysis of clinical data, RNA-binding protein (RBP) NOVA2 is identified as a pivotal LUAD metastasis-associated regulator. NOVA2 expression is elevated in metastatic LUAD tissues and correlates with poor prognosis of LUAD patients. Functionally, NOVA2 depletion suppresses epithelial-mesenchymal transition (EMT), migration, and invasion in vitro, and attenuates LUAD cell metastasis in vivo. Mechanistically, histone acetyltransferase p300 augments H3K27 acetylation level and facilitates the binding of STAT3 to the NOVA2 promoter, which in turn promotes NOVA2 transcription. Increased NOVA2 expression induces exon skipping (exons 6–7) in SMAD4 to generate a truncated splicing isoform (termed Δ-SMAD4). The resulting Δ-SMAD4 isoform evades E3 ubiquitin ligase β-TrCP-mediated ubiquitination, maintaining its ability to form complex with SMAD3 (R-SMAD) and sustain TGF-β/SMAD signaling. Moreover, in NOVA2-overexpressing LUAD cells, Δ-SMAD4 knockdown has stronger inhibitory effects on TGF-β-induced EMT and invasion than does SMAD4 knockdown. In summary, our findings identify a novel mechanism by which STAT3-mediated transcriptional upregulation of NOVA2 promotes SMAD4 splicing in metastatic LUAD, and suggest that the STAT3-NOVA2-Δ-SMAD4 axis drives EMT and LUAD metastasis, which may be a promising therapeutic target for treating LUAD.

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Fig. 1: Identification of metastatic LUAD-associated NOVA2.
Fig. 2: NOVA2 promotes LUAD cell EMT and metastasis.
Fig. 3: STAT3 promotes NOVA2 transcriptional activity in LUAD cells.
Fig. 4: p300 upregulation enhances the binding of STAT3 to NOVA2 promoter.
Fig. 5: NOVA2 is involved in TGF-β signaling pathway.
Fig. 6: NOVA2 regulates SMAD4 mRNA splicing in LUAD cells.
Fig. 7: β-TrCP-mediated Δ-SMAD4 ubiquitination is diminished and Δ-SMAD4 facilitates TGF-β-induced EMT and invasion of LUAD cells.
Fig. 8: STAT3 inhibitor galiellalactone attenuates lung metastasis and NOVA2/SMAD4 expression in a murine model of A549-M cell metastasis.

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Data availability

The data generated in Fig. 1A are retrieved from EuRBPDB [26], ATtRACT [27], CancerSEA [28], and prognostic gene signatures [29] online databases. The gene expression correlation analyzed in Fig. 4F, S3E and S3F are available from GEPIA database (http://gepia.cancer-pku.cn/). The RNA-seq data generated in Figs. 5A and 6A are included in supplementary materials, and all other raw data are available upon request from the corresponding author.

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Acknowledgements

We are grateful for the participation and cooperation from LUAD patients. This work was supported in part by National Natural Science Foundation of China (82273372, 82203773, 82303450), and the Natural Science Foundation of Jiangsu Province (BK20231233, BK20220250), and the “Qinglan Project” of Jiangsu Province universities, and the Talent Project of Kangda College of Nanjing Medical University (KD2024JXJH001), and Suzhou Key Laboratory for Molecular Cancer Genetics (SZS201209), and Collaborative Innovation Center of Molecular Medicine between Soochow University and Donghai County People’s Hospital (H230470), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Author notes

  1. These authors contributed equally: Shengjie Wang, Xin Tong, Runfeng Sun, Xinyi Xia, Donglai Chen, Zhao Wang.

Authors and Affiliations

  1. Department of Basic Medicine, Kangda College of Nanjing Medical University; Lianyungang Medical-Education Innovation and Research Center, Nanjing Medical University, Lianyungang, Jiangsu Province, China

    Shengjie Wang, Xiaoxiao Guo & Die Hu

  2. Collaborative Innovation Center of Molecular Medicine between Soochow University and Donghai County People’s Hospital, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China

    Shengjie Wang, Runfeng Sun & Hong-Tao Zhang

  3. Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China

    Xin Tong, Chenzhuo Wu & Hong-Tao Zhang

  4. Donghai County People’s Hospital, Lianyungang, Jiangsu Province, China

    Runfeng Sun

  5. Institute of Laboratory Medicine, Nanjing Jinling Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China

    Xinyi Xia

  6. State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu Province, China

    Xinyi Xia

  7. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Donglai Chen

  8. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China

    Zhao Wang

  9. Department of Medical Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China

    Hao Shi & Hong-Tao Zhang

  10. Soochow University Laboratory of Cancer Molecular Genetics, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China

    Hao Shi & Hong-Tao Zhang

  11. Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, Jiangsu Province, China

    Hao Shi & Hong-Tao Zhang

  12. Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang Province, China

    Ersuo Jin

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  1. Shengjie Wang
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Contributions

SW, EJ, and H-TZ contributed to study concept and design. SW, XT, RS, XX, DC, and ZW performed all the experiments. HS, CW, XG, and DH provided technical support. SW, EJ, and H-TZ analyzed the data, wrote the manuscript, and contributed to the interpretation of data and critical revision of the manuscript. SW, XT, and H-TZ provided the funding and supervised the study.

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Correspondence to Shengjie Wang, Ersuo Jin or Hong-Tao Zhang.

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Human LUAD tissues were obtained after informed consent was available from all patients. The study protocol was carried out in accordance with the ethical principles outlined in the Declaration of Helsinki and has been approved by the Ethics Committee of Soochow University.

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Wang, S., Tong, X., Sun, R. et al. STAT3-mediated transactivation of NOVA2 promotes lung adenocarcinoma metastasis by splicing SMAD4. Oncogene (2026). https://doi.org/10.1038/s41388-026-03752-6

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