A Study of PKCα-mediated nuclear translocation of cGAS stabilizes β-catenin and drives metastasis. Qimin Zhang et al
Description
Although recent studies have shown that 2′3′-cyclic GMP-AMP synthase (cGAS) has both canonical cytoplasmic and noncanonical 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 metastatic dissemination in triple-negative breast cancer (TNBC). Cytosolic 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), an E3 ubiquitin ligase, thereby preventing β-catenin ubiquitination and promoting its stabilization. This, in turn, activates Wnt/β-catenin signaling. PKCα thus acts as a key regulator of this non-canonical, cGAS-driven metastatic pathway. Therapeutic TAT peptides designed to inhibit cGAS phosphorylation significantly reduce metastatic dissemination. 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.