Metastasis-associated protein 1 rewires prostate cancer transcriptomes via direct RNA interactions governing gene expression and alternative splicing

Objective This study investigated whether metastasis-associated protein 1 (MTA1) acts as an RNA-binding protein to directly regulate gene expression and alternative splicing in prostate cancer, thereby exploring its dual transcriptional and post-transcriptional roles. Methods MTA1-stable-knockdown PC-3 cells were subjected to RNA sequencing and formaldehyde RNA immunoprecipitation sequencing to characterize the MTA1–RNA interactome and its functional significance. Results MTA1 knockdown dysregulated 1248 genes and 2367 alternative splicing events. Differentially expressed genes were enriched in extracellular matrix remodeling, PI3K–Akt signaling, and hypoxia-response pathways, whereas alternatively spliced genes were associated with spliceosome and RNA-processing pathways. Formaldehyde RNA immunoprecipitation sequencing confirmed MTA1 binding to GC-rich RNA motifs, with significant overlap between MTA1-bound targets and dysregulated genes or splicing events. Representative findings included MTA1 binding to the 3′ untranslated region of COL6A1, resulting in its downregulation, and regulation of SNHG17 splicing, indicating direct roles in RNA stability and splicing regulation. Conclusion MTA1 functions as both an epigenetic modulator and an RNA-binding protein in prostate cancer, directly regulating RNA networks that promote tumor progression. These findings reveal novel RNA-mediated oncogenic mechanisms and highlight the therapeutic potential of MTA1 in prostate cancer.