The PRC2 and PRC1 complexes are aberrantly expressed in human cancers and have been linked to decreases in patient survival. MUC1-C is an oncoprotein that is also overexpressed in diverse human cancers and is associated with a poor prognosis. Recent studies have supported a previously unreported function for MUC1-C in activating PRC2 and PRC1 in cancer cells. In the regulation of PRC2, MUC1-C (i) drives transcription of the EZH2 gene, (ii) binds directly to EZH2, and (iii) enhances occupancy of EZH2 on target gene promoters with an increase in H3K27 trimethylation. Regarding PRC1, which is recruited to PRC2 sites in the hierarchical model, MUC1-C induces BMI1 transcription, forms a complex with BMI1, and promotes H2A ubiquitylation. MUC1-C thereby contributes to the integration of PRC2 and PRC1-mediated repression of tumor suppressor genes, such as CDH1, CDKN2A, PTEN and BRCA1. Like PRC2 and PRC1, MUC1-C is associated with the epithelial-mesenchymal transition (EMT) program, cancer stem cell (CSC) state, and acquisition of anticancer drug resistance. In concert with these observations, targeting MUC1-C downregulates EZH2 and BMI1, inhibits EMT and the CSC state, and reverses drug resistance. These findings emphasize the significance of MUC1-C as a therapeutic target for inhibiting aberrant PRC function and reprogramming the epigenome in human cancers.

中文翻译：

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MUC1-C激活多梳抑制复合物并下调人类癌细胞中的肿瘤抑制基因。

PRC2和PRC1复合物在人类癌症中异常表达，并与患者存活率下降有关。MUC1-C是一种癌蛋白，在多种人类癌症中也过表达，并且与不良预后相关。最近的研究支持了MUC1-C先前未报道的激活癌细胞中PRC2和PRC1的功能。在PRC2的调控中，MUC1-C（i）驱动EZH2基因的转录，（ii）直接与EZH2结合，并且（iii）通过增加H3K27三甲基化来增强EZH2在靶基因启动子上的占有率。对于在层次模型中被募集到PRC2位点的PRC1，MUC1-C诱导BMI1转录，与BMI1形成复合体，并促进H2A泛素化。因此，MUC1-C有助于整合PRC2和PRC1介导的抑癌基因抑制，例如CDH1，CDKN2A，PTEN和BRCA1。像PRC2和PRC1一样，MUC1-C与上皮-间质转化（EMT）程序，癌症干细胞（CSC）状态以及抗癌药耐药性的获得有关。与这些观察结果一致，靶向MUC1-C下调EZH2和BMI1，抑制EMT和CSC状态，并逆转耐药性。这些发现强调了MUC1-C作为抑制人癌症中PRC功能异常和重编程表观基因组的治疗靶标的重要性。并逆转耐药性。这些发现强调了MUC1-C作为抑制人癌症中PRC功能异常和重编程表观基因组的治疗靶标的重要性。并逆转耐药性。这些发现强调了MUC1-C作为抑制人癌症中PRC功能异常和重编程表观基因组的治疗靶标的重要性。