EYA1 promotes tumor angiogenesis in colorectal cancer by activating HIF-1β through LSD2-mediated H3K4me2 demethylation.

Abstract

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide, with tumor angiogenesis playing a crucial role in its progression. The Drosophila Eyes Absent Homologue 1(Eya1) has been implicated in various cancers, but its mechanism in CRC angiogenesis remains unclear. This study explores the mechanism by which Eya1 regulates angiogenesis in CRC by activating HIF-1β through Lysine-specific demethylases 2 (LSD2).

Methods: CRC tissues and cell lines were analyzed to assess Eya1 and LSD2 using qPCR and Western blot. VEGFA expression and endothelial cell proliferation were measured using ELISA and tube formation assays. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays were used to investigate protein interactions and histone modifications.

Results: We found that Eya1 and LSD2 were significantly upregulated in CRC tissues and cell lines. Eya1 overexpression increased VEGFA expression and promoted endothelial cell proliferation and tube formation, and the effects were abolished upon silencing LSD2 or HIF-1β. Additionally, Eya1 was shown to interact with Dach1, a co-stimulatory factor, to regulate LSD2 expression and its activity in promoting HIF-1β-mediated angiogenesis.

Conclusion: This study demonstrates that Eya1 promotes CRC angiogenesis through the LSD2/HIF-1β/VEGF pathway. These findings identify a novel mechanism of angiogenesis regulation in CRC, suggesting that targeting the Eya1-LSD2-HIF-1β axis may provide new therapeutic strategies for CRC treatment.