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

Qimin Zhang1, Chao Tong2, Manyu Zhao2

  • 1Department 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.

Molecular Cell
|June 18, 2026
PubMed

Insights

Nuclear 2'3'-cyclic GMP-AMP synthase (cGAS) promotes triple-negative breast cancer (TNBC) metastasis via Wnt/β-catenin signaling. Inhibiting cGAS phosphorylation reduces metastasis, highlighting it as a potential therapeutic target for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • 2'3'-cyclic GMP-AMP synthase (cGAS) has known cytoplasmic and nuclear functions.
  • The role of nuclear cGAS in cancer metastasis, particularly in triple-negative breast cancer (TNBC), is not well understood.

Purpose of the Study:

  • To elucidate the mechanism by which nuclear cGAS contributes to TNBC metastasis.
  • To identify key regulators and potential therapeutic targets in this pathway.

Main Methods:

  • Investigated the STING-independent role of nuclear cGAS in TNBC metastasis.
  • Utilized phosphorylation site mapping (Ser120) and protein interaction studies.
  • Employed therapeutic transactivator of transcription (TAT) peptides to inhibit cGAS phosphorylation.
  • Analyzed clinical TNBC cohorts for correlation between nuclear cGAS expression and metastasis.

Main Results:

  • Identified a novel pathway where Protein kinase C alpha (PKCα) phosphorylates nuclear cGAS at Ser120, promoting TNBC metastasis.
  • Nuclear cGAS disrupts the β-catenin/TRIM33 interaction, stabilizing β-catenin and activating Wnt/β-catenin signaling.
  • Inhibition of cGAS phosphorylation by TAT peptides significantly reduced metastasis in preclinical models.
  • Elevated nuclear cGAS expression in clinical TNBC samples correlated with increased metastatic potential.

Conclusions:

  • A PKCα-cGAS-TRIM33 axis regulates nuclear β-catenin stability and promotes TNBC metastasis independently of STING.
  • cGAS phosphorylation is a critical step in this non-canonical metastatic pathway.
  • Targeting cGAS phosphorylation presents a promising theranostic strategy for TNBC metastasis.
Keywords:
metastasisnuclear cGAStriple-negative breast cancerubiquitinationβ-catenin

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