Alphavirus M1 disrupts super-enhancer-driven oncogenic transcription in osteosarcoma [RNA-seq]

This study provides the first evidence of the potent oncolytic activity of M1, a natural Getah-like alphavirus, against OS. We demonstrate that OS cells exhibit heightened sensitivity to M1 infection, with its anti-tumor effects not solely dependent on the canonical ER stress-induced apoptosis.

Proteomic and ChIP-seq analyses show the DNA-directed RNA polymerase II subunit RPB1 contributes to oncogenic super-enhancer activity and serves as a direct target of M1-mediated regulation. The oncolytic potency correlated positively with the transcriptional dependency on RPB1 within super-enhancer regions. Mechanistically, the viral non-structural protein NSP2 disrupts super-enhancer activity by recruiting the CUL2-RBX1-ELOC complex, which triggers K63-linked ubiquitination and degradation of RPB1.