ACTB promotes ESCC progression by regulating the AKT-mTOR signaling pathway through an m6A-dependent mechanism.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis, and the upstream regulatory mechanisms driving oncogenic signaling remain insufficiently defined. In this study, we identify a previously unrecognized nuclear function of the cytoskeletal protein ACTB in promoting ESCC progression. We show that ACTB translocates to the nucleus and directly binds to the promoter of the m6A reader gene YTHDC2, transcriptionally activating its expression. YTHDC2, in turn, binds to m6A-modified sites on AKT mRNA, preventing its degradation and enhancing its stability. This results in sustained activation of the PI3K-AKT-mTOR signaling pathway, a key oncogenic cascade that promotes tumor growth and survival. Integrated CUT&Tag and RNA-seq analyses revealed a direct ACTB-YTHDC2 transcriptional axis, while RNA immunoprecipitation and MeRIP-qPCR confirmed YTHDC2-AKT interaction via m6A recognition. Functional assays in ESCC cell lines, patient-derived organoids, and xenograft mouse models demonstrated that both ACTB and YTHDC2 are essential for ESCC proliferation and tumorigenicity. Notably, pharmacological inhibition of mTOR with rapamycin effectively suppressed ACTB-driven tumor phenotypes in vitro and in vivo, supporting the therapeutic relevance of this signaling axis. Together, our findings define a novel ACTB-YTHDC2-AKT-mTOR regulatory network that integrates transcriptional and epitranscriptomic control in ESCC. This study reveals a noncanonical nuclear role for ACTB and identifies a mechanistically tractable pathway that may be exploited for targeted therapy in ACTB-driven esophageal cancer.