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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月1日

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  • 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

摘要

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.