MTA1 Rewires Prostate Cancer Transcriptomes: Direct RNA Interactions Govern Oncogenic Gene Expression and Splice Variant Networks [RNA-Seq]

MTA1, a well-characterized epigenetic modifier, plays pivotal roles in cancer progression. However, its involvement in RNA-mediated regulatory mechanisms remains poorly understood. This study unveils MTA1's dual functionality as a chromatin remodeler and RNA-binding protein (RBP) in prostate cancer (PCa) pathogenesis. By integrating RNA sequencing (RNA-seq) and formaldehyde-crosslinking RNA immunoprecipitation sequencing (fRIP-seq) in PC-3 cells, we demonstrate that MTA1 knockdown dysregulates 1,248 genes and modulates 2,367 alternative splicing events (ASEs). Functional annotation links MTA1-associated differentially expressed genes (DEGs) to extracellular matrix (ECM) remodeling, PI3K-Akt signaling, and hypoxia responses, while ASEs implicate spliceosome activity and RNA processing pathways. fRIP-seq identifies direct MTA1-bound RNAs enriched with GC-rich motifs, with integrative analyses revealing significant overlaps between MTA1 RNA targets and DEGs/ASEs. Our findings establish MTA1 as a multifunctional RBP bridging transcriptional and post-transcriptional networks, offering novel mechanistic insights into PCa progression. Overall design: This study utilized prostate cancer PC-3 cells as the model system to systematically investigate the role of MTA1 in transcriptional and post-transcriptional regulation through MTA1 knockdown (KD) combined with RNA-seq and fRIP-seq analyses. RNA-seq identified 1,248 differentially expressed genes (DEGs) and 2,367 alternative splicing events (ASEs). Functional analysis revealed that DEGs were primarily enriched in ECM remodeling, PI3K-Akt signaling, and hypoxia response, while ASEs were associated with spliceosome activity and RNA processing. fRIP-seq identified MTA1 directly bound RNAs, which exhibited a preference for GC-rich motifs, and integrative analysis demonstrated significant overlap between MTA1 RNA targets and DEGs/ASEs. These findings confirm MTA1's dual functionality as an RNA-binding protein (RBP) in transcriptional and splicing regulation, providing novel mechanistic insights into prostate cancer progression.