Cell-cycle-related transcriptional factor DLX4: a novel prognostic biomarker and potential therapeutic target in colorectal cancer

Abstract Distal - less homeobox 4 (DLX4) is a transcription factor vital for embryonic development and shows pro - oncogenic properties in some hematological and solid tumors. In colorectal cancer (CRC), its molecular function and contributions to tumorigenesis remain to be explored. Using bulk, single - cell and spatial transcriptomics, we assessed DLX4’s clinicopathological significance and its impact on the tumor immune microenvironment (TIME). Our results show DLX4 is highly expressed in CRC, correlating with poor prognosis in multi - center cohorts and is also related to a cytotoxic T lymphocyte (CTL) dysfunction - related immunosuppressive microenvironment. Transcriptomic and proteomic analyses identified DLX4 - associated cell signaling. In vitro, we confirmed DLX4 promotes cell proliferation, cell - cycle transitions and suppresses apoptosis. Furthermore, we found its key transcriptional target ZC3HC1 via ChIP – seq analysis, ChIP - qPCR and luciferase assay. Notably, DLX4 has strong potential for liquid - liquid phase separation and likely forms condensates when binding to ZC3HC1’s promoter, a crucial cell - cycle regulator. Overall, DLX4 is a novel prognostic biomarker and suggests potential CRC therapeutic strategies, making significant contributions to the understanding and potential treatment of CRC at the molecular level.