药物抗性癌细胞（CSCs）的根除为化疗或靶向治疗后的局部肿瘤控制提供了可能性。作为主要的药物抗性标记，ABCG2也对结肠直肠癌（CRC）进化至关重要，尤其是对癌干细胞样特性的扩展。迄今为止，关于ABCG2表达调控的知识，特别是其上游转录调控机制在肿瘤中，包括CRC中，仍然有限。在本研究中，发现ABCG2在CRC癌干细胞（cCSCs）扩展和耐药性的CRC组织中明显上调，并与CRC复发密切相关。在机制上，识别TOX3作为特异性转录因子，通过结合ABCG2启动子区域的-261到-141段，促进ABCG2的表达和随后的cCSCs扩展及耐药性。此外，我们发现TOX3招募WDR5促进cCSCs中ABCG2启动子的H3K4三甲基化，进一步赋予CRC干细胞样特性和化疗耐药性，通过共调节ABCG2的转录。与此观察一致的是，TOX3、WDR5和ABCG2在原位CRC小鼠模型的耐药性肿瘤组织中显示异常激活，临床调查进一步证明了综合评估TOX3、WDR5和ABCG2可成为预测CRC患者复发或转移生存的更有效策略。因此，我们的研究发现了TOX3-WDR5/ABCG2信号通路在调控CRC干细胞样特性和化疗耐药性中起到重要作用，并且化疗联合WDR5抑制剂可能会导致ABCG2异常表达肿瘤的合成致死性。版权：© 2023 Hao等。本文为开放获取文章，依据创作共享许可证进行分发，允许在任何媒体中无限制使用、分发和复制，只要原始作者和出处得到适当的表示。

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.Copyright: © 2023 Hao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.