Tagde Ashujit, Markert Tahireh, Rajabi Hasan, Hiraki Masayuki, Alam Maroof, Bouillez Audrey, Avigan David, Anderson Kenneth, Kufe Donald
Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Oncotarget. 2017 Aug 10;8(41):69237-69249. doi: 10.18632/oncotarget.20144. eCollection 2017 Sep 19.
The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives transcription by a MYC-dependent mechanism. MUC1-C thus promotes MYC occupancy on the promoter and thereby activates BMI1 expression. We also show that the MUC1-C→MYC pathway induces RING2 expression. Moreover, in contrast to BMI1 and RING2, we found that MUC1-C drives RING1 by an NF-κB p65-dependent mechanism. Targeting MUC1-C and thereby the suppression of these key PRC1 proteins was associated with downregulation of the PRC1 E3 ligase activity as evidenced by decreases in ubiquitylation of histone H2A. Targeting MUC1-C also resulted in activation of the PRC1-repressed tumor suppressor genes, and . These findings identify a heretofore unrecognized role for MUC1-C in the epigenetic regulation of MM cells.
多梳抑制复合物1（PRC1）包含BMI1、RING1和RING2蛋白。BMI1是多发性骨髓瘤（MM）细胞存活所必需的。MUC1-C癌蛋白在MM细胞中异常表达，激活MYC，也是MM细胞存活所必需的。目前的研究表明，用（i）稳定且可诱导的沉默和CRISPR/Cas9编辑以及（ii）阻断MUC1-C功能的药物抑制剂GO-203靶向MUC1-C，可下调BMI1、RING1和RING2的表达。结果表明，MUC1-C通过MYC依赖性机制驱动转录。因此，MUC1-C促进MYC在启动子上的占据，从而激活BMI1的表达。我们还表明，MUC1-C→MYC途径诱导RING2的表达。此外，与BMI1和RING2不同，我们发现MUC1-C通过NF-κB p65依赖性机制驱动RING1。靶向MUC1-C从而抑制这些关键的PRC1蛋白与PRC1 E3连接酶活性的下调有关，这通过组蛋白H2A泛素化的减少得到证明。靶向MUC1-C还导致PRC1抑制的肿瘤抑制基因的激活。这些发现揭示了MUC1-C在MM细胞表观遗传调控中迄今未被认识的作用。
