Smarca1维持PAX3-FOXO1融合癌基因并通过染色质重塑协调EMT网络

Aggressive fusion positive rhabdomyosarcoma driven by the PAX3-FOXO1 oncogene remains therapeutically challenging with poor outcomes. High SMARCA1 expression marked poorer survival outcomes, indicating prognostic significance. The chromatin remodeling factor SMARCA1 shows preferential expression in fusion positive tumors, yet its functional role in sustaining oncogenic programs has not been defined. SMARCA1 function was investigated using CRISPR Cas9 knockout combined with multi-omics profiling. All detected PAX3-FOXO1 transcripts became undetectable, showing that SMARCA1 is required for fusion expression. Fusion transcript abundance showed nearly perfect quantitative correlation with downstream key oncogenic targets including FGFR4, SNAI2, MYOD1, MYCN, ALK, ID2, IGF2, and CXCR4. Fusion levels determine the magnitude of its transcriptional output. My prior findings established, SMARCA1 acts as a master coordinator of epithelial mesenchymal transition (EMT) networks. Knockout caused simultaneous suppression of all four core EMT transcription factors SNAI1, SNAI2, ZEB1, and ZEB2 which represent both direct and indirect targets of the fusion oncogene. Their upstream regulatory pathways collapsed concurrently, including complete loss of canonical SMAD dependent TGF-beta signaling and multiple non canonical branches involving PI3K, AKT, RAS, MAPK, mTOR, and NF-κB pathways. WNT/beta-catenin signaling was likewise dismantled. Despite the elimination of detectable PAX3-FOXO1 mRNA, suppression of EMT transcription factors, and collapse of their upstream signaling networks, EMT gene signatures paradoxically showed strong enrichment with elevated mesenchymal markers. However, this fusion independent EMT transcriptional state failed to produce functional cellular plasticity. Migration was abolished and invasion markedly impaired, indicating that transcriptional activation alone is insufficient without proper chromatin architecture. Building on our earlier observation that SMARCA1 regulates EMT pathways, our profiling indicates that YAP-TAZ-TEAD remains active as a fusion-independent EMT module despite the collapse of the canonical fusion-driven EMT network. These findings establish that SMARCA1 maintains PAX3-FOXO1 expression and governs the organization of EMT transcription factor networks together with their upstream signaling dependencies. Together, these findings show that SMARCA1 is required to maintain PAX3-FOXO1 expression, organize EMT transcription factor networks and their upstream signaling pathways, and demonstrate that chromatin architecture is essential for converting transcriptional programs into functional behavior, and reveal chromatin dependency as a targetable vulnerability in fusion driven cancers, effectively transforming the historically undruggable PAX3-FOXO1 fusion into a druggable chromatin dependent weakness.<!--EndFragment-->