Lung cancer is the most lethal malignancies with high aggressive and poor prognosis. Until now, the five-year survival rate has not been improved which brings serious challenge to human health. Lung cancer stem cells (LCSCs) serve as the root of cancer occurrence, progression, recurrence, and drug resistance. Therefore, effective anti-cancer agents and molecular mechanisms which could specifically eliminate LCSCs are urgently needed for drug design. In this article, we discovered Olig2 was overexpressed in clinical lung cancer tissues and acted as a transcription factor to regulate cancer stemness by regulating CD133 gene transcription. The results suggested Olig2 could be a promising target in anti-LCSCs therapy and new drugs targeted Olig2 may exhibit excellent clinical results. Furthermore, we verified ACT001, a guaianolide sesquiterpene lactone in phase II clinical trial with excellent glioma remission, inhibited cancer stemness by directly binding to Olig2 protein, inducing Olig2 ubiquitination degradation and inhibiting CD133 gene transcription. All these results suggested that Olig2 could be an excellent druggable target in anti-LCSCs therapy and lay a foundation for the further application of ACT001 in the treatment of lung cancer in clinical.

肺癌是最致命的恶性肿瘤，具有高侵袭性和不良预后。迄今为止，五年生存率仍未得到改善，给人类健康带来严峻挑战。肺癌干细胞（LCSCs）是癌症发生、进展、复发和耐药的根源。因此，药物设计迫切需要能够特异性消除LCSCs的有效抗癌剂和分子机制。在这篇文章中，我们发现 Olig2 在临床肺癌组织中过表达，并作为转录因子通过调节 CD133 基因转录来调节癌症干性。结果表明，Olig2 可能是抗 LCSCs 治疗的一个有前途的靶点，靶向 Olig2 的新药可能表现出优异的临床效果。此外，我们验证了 ACT001，一种正在进行II期临床试验的愈创木酚内酯倍半萜内酯，具有优异的胶质瘤缓解作用，通过直接结合Olig2蛋白，诱导Olig2泛素化降解和抑制CD133基因转录来抑制癌症干性。这些结果表明Olig2可能成为抗LCSCs治疗的优良药物靶点，为ACT001在临床上进一步应用于肺癌治疗奠定了基础。