Alphavirus M1 disrupts super-enhancer-driven oncogenic transcription via non-structural protein NSP2 in osteosarcoma
- Jiajun Zhang
- Lifeng Yin
- Qianqian Han
- Yuanyuan Li
- Fei Wu
- Shanyu Huang
- Jiayu Zhang
- Yiwei Fu
- Guanyu Huang
- Yu Xu
- Hanxiao Yin
- Jiankai Liang
- Wenbo Zhu
- Yuan Lin
- Guangmei Yan
- Junqiang Yin
- Jingnan Shen
- Jing Cai
- Weihai Liu
2026-07-01
Oncolytic virotherapy has shown promise for various cancers, but its application in osteosarcoma (OS) remains underexplored. This study provides evidence that M1, a natural Getah-like alphavirus, exerts oncolytic activity 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. Together, these findings uncover a previously unrecognized mechanism underlying M1 activity in osteosarcoma, support further preclinical evaluation of M1 in this setting, and identify RPB1 as a candidate biomarker for virotherapy response.