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

Abstract. The subcellular localization, together with the expression level, determines the biological effects and physiological 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. Here, we observed FIGN largely in the cytoplasm of malignant cells, and increased cytoplasmic FIGN was significantly associated with clinicopathological 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 MYH2 and HNRNPA2B1; MYH2 regulated the nucleocytoplasmic distribution of FIGN and its effects on cancer progression, while cytoplasmic FIGN stabilized 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.