Given that colorectal cancer stem cells (CCSCs) play key roles in the tumor dormancy, metastasis, and relapse, targeting CCSCs is a promising strategy in cancer therapy. Here, we aimed to identify the new regulators of CCSCs and found that Cullin 4B (CUL4B), which possesses oncogenic properties in multiple solid tumors, drives the development and metastasis of colon cancer by sustaining cancer stem-like features. Elevated expression of CUL4B was confirmed in colon tumors and was associated with poor overall survival. Inhibition of CUL4B in cancer cell lines and patient-derived tumor organoids led to reduced sphere formation, proliferation and metastasis capacity. Mechanistically, CUL4B coordinates with PRC2 complex to repress miR34a expression, thus upregulates oncogenes including MYCN and NOTCH1, which are targeted by miR34a. Furthermore, we found that elevated CUL4B expression is associated with miR34a downregulation and upregulation of miR34a target genes in colon cancer specimens. Collectively, our findings demonstrate that CUL4B functions to repress miR34a in maintaining cancer stemness in CRC and provides a potential therapeutic target.

中文翻译：

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CUL4B通过抑制结直肠癌中的肿瘤抑制因子miR34a来促进癌症的发展。

考虑到结直肠癌干细胞（CCSC）在肿瘤休眠，转移和复发中起关键作用，靶向CCSC是癌症治疗中一种有前途的策略。在这里，我们旨在确定CCSC的新调节剂，并发现在多个实体瘤中具有致癌特性的Cullin 4B（CUL4B）通过维持癌干样特征来驱动结肠癌的发展和转移。在结肠肿瘤中证实了CUL4B的表达升高，并且与较差的总生存期有关。CUL4B在癌细胞系和患者来源的肿瘤类器官中的抑制作用导致球形成，增殖和转移能力降低。从机制上讲，CUL4B与PRC2复合体协同抑制miR34a的表达，从而上调了miR34a靶向的癌基因，包括MYCN和NOTCH1。此外，我们发现升高的CUL4B表达与结肠癌标本中的miR34a下调和miR34a靶基因上调相关。总的来说，我们的研究结果表明CUL4B在维持CRC中的癌症干性方面具有抑制miR34a的功能，并提供了潜在的治疗靶点。