FOXK1 drives colorectal cancer progression by transcriptionally activating GRB2.

Colorectal cancer (CRC) represents a leading cause of global cancer-related mortality. Despite substantial therapeutic advancements, persistent challenges of local recurrence and distant metastasis continue to compromise patient survival outcomes. Tumorigenesis and progression are orchestrated through complex signal transduction networks. It is imperative to delineate critical signaling pathways in CRC for identifying novel therapeutic targets. Transcription factor forkhead box 1 (FOXK1) and adaptor protein growth factor receptor-bound protein 2 (GRB2) regulate tumor initiation and progression across diverse malignancies. However, their functional interplay and precise mechanistic contributions in CRC remain elusive. In this study, FOXK1 overexpression promoted cellular proliferation and metastatic dissemination in CRC models. And it is correlated significantly with adverse clinical prognosis. Mechanistically, FOXK1 transcriptionally activates GRB2 by directly binding to its promoter region, thereby driving the malignant phenotype of CRC. These findings elucidate the FOXK1/GRB2 signaling axis. And they provide unprecedented insights into transcriptional regulatory networks governing CRC pathogenesis. As multifunctional signaling hubs, both FOXK1 and GRB2 represent promising candidates for molecularly targeted CRC therapies.