Alphavirus M1 disrupts super-enhancer-driven oncogenic transcription via non-structural protein NSP2 in osteosarcoma.

Authors

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

Published in

Nature communications. Jul 01, 2026. Epub Jul 01, 2026.

Abstract

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.

PMID:
42386745
Bibliographic data and abstract were imported from PubMed on 02 Jul 2026.

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