2. Academic Validation
  3. The cytoskeletal protein smoothelin maintains homologous recombination repair by stabilizing RAD51 in an HUWE1-dependent manner in colorectal cancer

The cytoskeletal protein smoothelin maintains homologous recombination repair by stabilizing RAD51 in an HUWE1-dependent manner in colorectal cancer

  • Acta Pharm Sin B. 2025 Dec;15(12):6444-6460. doi: 10.1016/j.apsb.2025.09.042.
Wei Xu 1 2,  Minmin Shen 1 3,  Junjie Ma 1 2,  Chuanlin Peng 4,  Shanshan Wu 1 2,  Xinxin Yang 1 2,  Jiahe Wu 2 5,  Youyou Yan 2,  Nengming Lin 1 2 6,  Jianqing Gao 5,  Bo Zhang 1 2 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China.
  • 2 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
  • 3 Department of Drug Clinical Trial Institution, Huzhou Central Hospital, Huzhou 313000, China.
  • 4 Department of Gastrointestinal Surgery, the Third People's Hospital of Yuhang District, Hangzhou 311115, China.
  • 5 Institute of Pharmaceutics, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 6 Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou 310024, China.
PMID: 41477349 DOI: 10.1016/j.apsb.2025.09.042
Abstract

Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal Cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin Ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.

Keywords

Chemosensitization; Colorectal cancer; Cytoskeletal protein; DNA damage; Fuzuloparib; HR-mediated DNA repair; Irinotecan; RAD51.

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