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TIAL1 regulates the Hippo pathway through an RNA-binding-independent mechanism

Oncogene volume 45, pages 1941–1951 (2026)Cite this article

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Abstract

The Hippo pathway is an evolutionarily conserved signaling cascade whose dysregulation is implicated in a wide range of diseases. While many RNA-binding proteins (RBPs) regulate this pathway through canonical functions such as modulating mRNA stability and translation, the potential for RBP-mediated regulation via non-canonical, RNA-binding-independent mechanisms remains poorly defined. Here, we report that the RBP TIAL1 exhibits oncogenic properties in hepatocellular carcinoma, promoting cancer cell proliferation, migration, and invasion. Mechanistically, TIAL1 directly interacts with the core Hippo component SAV1, disrupting the MST1-SAV1 interaction and thereby suppressing Hippo signaling and activating YAP. Notably, this regulatory function is independent of the RNA-binding activity of TIAL1. Furthermore, extracellular stimuli such as energy surplus and EGF significantly upregulate TIAL1 expression, linking microenvironmental cues to Hippo pathway dysregulation. Together, our results reveal a previously unrecognized, RNA-binding-independent mode of RBP-mediated regulation, in which TIAL1 serves as a molecular integrator that conveys extracellular signals to the Hippo pathway to drive hepatocellular carcinoma progression, providing potential avenues for therapeutic intervention.

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Fig. 1: TIAL1 promotes HCC progression.
The alternative text for this image may have been generated using AI.
Fig. 2: TIAL1 modulates Hippo pathway activity.
The alternative text for this image may have been generated using AI.
Fig. 3: TIAL1 promotes tumor growth in vivo.
The alternative text for this image may have been generated using AI.
Fig. 4: TIAL1 disrupts the MST1-SAV1 interaction.
The alternative text for this image may have been generated using AI.
Fig. 5: TIAL1 links external stimuli to the Hippo pathway.
The alternative text for this image may have been generated using AI.
Fig. 6: Model of the regulatory axis: external stimuli-TIAL1-Hippo pathway.
The alternative text for this image may have been generated using AI.

Data availability

All study data are included in the main text and supporting information.

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Acknowledgements

We thank the BioRender.com for creating the illustrations in Fig. 6. This work was supported by the National Natural Science Foundation of China (32370760, 32000547), Hunan Provincial Science and Technology Innovation Foundation (2023RC3132), Hunan Provincial Natural Science Foundation (2023JJ20029, 2026JJ50556), National Key Research and Development Program of China (2023YFC2605400, 2023YFC2605402), Hengyang Central Hospital-Hunan Normal University Health Science Center Joint Research Grant (HYCHHNU202503), Hunan Cancer Hospital-Hunan Normal University Health Science Center Joint Research Grant (HNUCRI2025003), Health Research Project of Hunan Provincial Health Commission (20253730), and Research Team for Reproduction Health and Translational Medicine of Hunan Normal University (2023JC101).

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Author notes

  1. These authors contributed equally: Qianlong Dai, Lei Lou, Xiaojie Zhu.

Authors and Affiliations

  1. The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, The Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, School of Basic Medicine, Hunan Normal University, Changsha, China

    Qianlong Dai, Lei Lou, Haotian Zhao, Yaxian Zhong, Shuchang Peng, Xinyue Hu, Ruohan Sun, Xiaotian Tang, Feng Gu, Xiyun Deng, Junhua Zhou & Xiaowei Guo

  2. Changsha Gene Editing Technique Innovation Center, Changsha, China

    Qianlong Dai, Lei Lou, Haotian Zhao, Yaxian Zhong, Feng Gu & Xiaowei Guo

  3. Department of Nuclear Medicine, Shanghai 10th People’s Hospital, School of Life Science and Technology, Tongji University, Shanghai, China

    Xiaojie Zhu, Kai Peng, Yingqun Zhou & Lei Xue

  4. Bioinformatics Center, College of Biology, Hunan University, Changsha, China

    Zixin Cai & Yirong Wang

  5. Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning, China

    Pengcheng Wei

  6. Changsha Stomatological Hospital, School of Stomatology, Hunan University of Chinese Medicine, Changsha, China

    Yanwen He

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  1. Qianlong Dai
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Contributions

Junhua Zhou, Lei Xue, Yirong Wang and Xiaowei Guo conceived and designed the experiments. Qianlong Dai, Lei Lou, Xiaojie Zhu, Haotian Zhao, Zixin Cai, Kai Peng, Pengcheng Wei, Shuchang Peng, Xinyue Hu, Ruohan Sun, Xiaotian Tang and Yingqun Zhou performed the experiments. Qianlong Dai, Lou Lei and Junhua Zhou analyzed the data. Feng Gu, Xinyun Deng, Yanwen He, Junhua Zhou and Yaxian Zhong provided technical assistance. Junhua Zhou and Xiaowei Guo wrote the manuscript.

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Correspondence to Junhua Zhou, Yirong Wang, Lei Xue or Xiaowei Guo.

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Dai, Q., Lou, L., Zhu, X. et al. TIAL1 regulates the Hippo pathway through an RNA-binding-independent mechanism. Oncogene 45, 1941–1951 (2026). https://doi.org/10.1038/s41388-026-03807-8

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