The P300/ETV4-WDR4 axis promotes colorectal cancer progression via m7G-mediated SPP1 mRNA stabilization and autophagy suppression

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer mortality. WD repeat domain 4 (WDR4), a key m7G methyltransferase, is implicated in tumor progression, but its role in CRC and regulatory mechanisms are unclear. This study explores how WDR4 drives CRC pathogenesis via m7G-mediated RNA stability and autophagy suppression. In this study, high WDR4 correlated with poor prognosis and promoted CRC proliferation/metastasis by suppressing autophagy. P300/ETV4 formed a transcriptional complex enhancing WDR4 expression via H3K27ac modification. WDR4-mediated m7G methylation stabilized SPP1 mRNA, whose overexpression rescued WDR4-knockdown phenotypes. In vivo, WDR4 knockdown inhibited tumor growth and metastasis while activating autophagy. In conclusion, the P300/ETV4-WDR4-m7G-SPP1 axis drives CRC progression by coupling epigenetic regulation, RNA modification, and autophagy inhibition, offering novel therapeutic targets.