Cytoplasmic Fidgetin Induces Noncanonical Activation of β-Catenin to Support Cancer Progression

The subcellular localization, together with the expression level, determines the biological effects and physiologic functions of proteins. Fidgetin (FIGN) is a microtubule-severing protein that plays a critical role in cytoskeletal dynamics, and it predominantly localizes in the nucleus in normal cells. In this study, we observed FIGN largely in the cytoplasm of malignant cells, and increased cytoplasmic FIGN was significantly associated with clinicopathologic features and poor prognosis in breast carcinoma, hepatocellular carcinoma, and lung adenocarcinoma. Cytoplasmic FIGN promoted tumor development, growth, and metastasis in multiple mouse models, and it facilitated proliferation, colony formation, migration, and invasion of multiple cancer cells in vitro. FIGN interacted with myosin heavy chain 2 (MYH2) and HNRNPA2B1; MYH2 regulated the nucleocytoplasmic distribution of FIGN and its effects on cancer progression, whereas cytoplasmic FIGN stabilized cadherin-associated protein β-1 (β-catenin) mRNA and promoted malignant biological behaviors in an HNRNPA2B1-dependent manner. Furthermore, an iRGD-fused peptide was designed to block the MYH2-FIGN interface, which facilitated FIGN translocation to the nucleus and suppressed cancer progression. Together, this study demonstrates a noncanonical mechanism for β-catenin activation by cytoplasmic FIGN that drives cancer progression.

β-catenin activation and tumor progression mediated by cytoplasmic FIGN is reversible using strategies to relocate FIGN to the nucleus, highlighting FIGN as a potential therapeutic target across multiple cancer types.