Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 15:e06367.
doi: 10.1002/advs.202506367. Online ahead of print.

TWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression

Liangmin Fu  1   2   3 , Wuyuan Liao  1   4 , Youyan Tan  2 , Hansen Lin  1 , Kun Ye  1 , Xinwei Zhou  1 , Mingjie Lin  1 , Kangbo Huang  5   6 , Minyu Chen  1 , Jietao Wei  2 , Haoqian Feng  1 , Yuhang Chen  1 , Jinwei Chen  1 , Bohong Guan  1 , Shan Li  7 , Zhengkun Zhang  1 , Anze Yu  1 , Zihao Feng  1 , Lizhen Zhang  1 , Guannan Shu  8 , Jun Lu  1 , Wei Chen  1 , Yihui Pan  9 , Jiefeng Yang  2 , Junhang Luo  1 , Li Luo  10
Affiliations

TWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression

Liangmin Fu et al. Adv Sci (Weinh). .

Abstract

Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib-resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes-associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor-promoting activity of TWF2. Furthermore, salvianolic acid E is identified as a small-molecule inhibitor of the TWF2-YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient-derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.

Keywords: Hippo signaling; TWF2; renal cell carcinoma; sunitinib resistance; tumor progression.

PubMed Disclaimer

References

    1. L. Bukavina, K. Bensalah, F. Bray, M. Carlo, B. Challacombe, J. A. Karam, W. Kassouf, T. Mitchell, R. Montironi, T. O'Brien, V. Panebianco, G. Scelo, B. Shuch, H. van Poppel, C. D. Blosser, S. P. Psutka, Eur. Urol. 2022, 82, 529.
    1. R. L. Siegel, T. B. Kratzer, A. N. Giaquinto, H. Sung, A. Jemal, CA‐Cancer J. Clin. 2025, 75, 10.
    1. H. Moch, M. B. Amin, D. M. Berney, E. M. Comperat, A. J. Gill, A. Hartmann, S. Menon, M. R. Raspollini, M. A. Rubin, J. R. Srigley, P. Hoon Tan, S. K. Tickoo, T. Tsuzuki, S. Turajlic, I. Cree, G. J. Netto, Eur. Urol. 2022, 82, 458.
    1. S. P. Kim, A. L. Alt, C. J. Weight, B. A. Costello, J. C. Cheville, C. Lohse, C. Allmer, B. C. Leibovich, J. Urol. 2011, 185, 2035.
    1. T. Powles, L. Albiges, A. Bex, E. Comperat, V. Grunwald, R. Kanesvaran, H. Kitamura, R. McKay, C. Porta, G. Procopio, M. Schmidinger, C. Suarez, J. Teoh, G. de Velasco, M. Young, S. Gillessen, Ann. Oncol. 2024, 35, 692.