PKCα-mediated nuclear translocation of cGAS stabilizes β-catenin and drives metastasis

  • Mol Cell. 2026 Jun 18;86(12):2294-2308.e7. doi: 10.1016/j.molcel.2026.05.023.
Qimin Zhang  1 ,  Chao Tong  2 ,  Manyu Zhao  2 ,  Mengru Ma  2 ,  Shan Huang  3 ,  Yan He  2 ,  Yuxuan Song  2 ,  Meijun Liu  2 ,  Lian Yi  2 ,  Fan Yao  4 ,  Jiangsha Zhao  5 ,  Daxing Gao  6 ,  Zhiyong Mao  7 ,  Li Ma  8 ,  Peijing Zhang  9
Affiliations
  • 1. Department of Pharmacy, Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
  • 2. National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430074, China.
  • 3. Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China.
  • 4. Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China.
  • 5. Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
  • 6. State Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of USTC, Centre Adv. Interdisciplinary Sci. & Biomed. IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei 230027, China.
  • 7. Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 8. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].
  • 9. Department of Pharmacy, Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: [email protected].
PMID: 42314650 DOI: 10.1016/j.molcel.2026.05.023
Abstract

Although recent studies have shown that 2'3'-cyclic GMP-AMP synthase (cGAS) has both canonical cytoplasmic and non-canonical nuclear functions, the role of nuclear cGAS in Cancer metastasis remains unclear. Here, we identify a STING-independent mechanism by which nuclear cGAS activates Wnt/β-catenin signaling to promote metastasis in triple-negative breast Cancer (TNBC). Protein kinase C alpha (PKCα) phosphorylates cGAS at Ser120, facilitating its nuclear translocation. Once in the nucleus, cGAS disrupts the interaction between β-catenin and tripartite motif-containing protein 33 (TRIM33), preventing β-catenin ubiquitination and promoting its stabilization, thereby activating Wnt/β-catenin signaling. PKCα thus acts as a key regulator of this non-canonical, cGAS-driven metastatic pathway. Therapeutic transactivator of transcription (TAT) peptides inhibiting cGAS phosphorylation significantly reduce metastasis. Clinically, elevated nuclear cGAS expression is associated with increased metastasis in TNBC cohorts. Together, these findings delineate a PKCα-cGAS-TRIM33 axis that regulates nuclear β-catenin stability and establish cGAS phosphorylation as a promising theragnostic target for TNBC metastasis.

Keywords
metastasis; nuclear cGAS; triple-negative breast cancer; ubiquitination; β-catenin.
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