MUC1-C Dictates JUN and BAF-Mediated Chromatin Remodeling at Enhancer Signatures in Cancer Stem Cells.
MUC1-C Dictates JUN and BAF-Mediated Chromatin Remodeling at Enhancer Signatures in Cancer Stem Cells.
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DOI：
10.1158/1541-7786.mcr-21-0672
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发表时间：
2022-04-01
期刊：
影响因子：
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通讯作者：
Kufe D
中科院分区：
文献类型：
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作者：
Bhattacharya A;Fushimi A;Yamashita N;Hagiwara M;Morimoto Y;Rajabi H;Long MD;Abdulla M;Ahmad R;Street K;Liu S;Liu T;Kufe D
致癌MUC 1-C蛋白促进去势抵抗性前列腺癌（CRPC）和三阴性乳腺癌（TNBC）细胞的去分化。染色质重塑对于癌症干细胞（CSC）状态至关重要;然而，没有明确的证据表明MUC 1-C调节染色质可及性，从而调节干细胞相关基因的表达。我们证明MUC 1-C驱动CRPC和TNBC细胞去分化中染色质结构的全局变化。我们的研究结果表明，MUC 1-C诱导差异可及区域（DAR）在他们的基因组，这是显着相关的差异表达基因（DEG）。基序和顺式组分析进一步证明MUC 1-C诱导的DAR与由转录因子的JUN/AP-1家族调节的基因对齐。MUC 1-C激活BAF染色质重塑复合物，该复合物在增强子选择中被JUN招募。在CRPC和TNBC细胞自我更新所需的NOTCH 1基因的研究中，我们证明MUC 1-C对于（i）JUN和ARID 1A/BAF的占用，（ii）H3 K27 ac和H3 K4 me 3信号的增加，以及（iii）近端增强子样标签上染色质可及性的开放是必需的。对EGR 1和LY 6 E干细胞相关基因的研究进一步证明，MUC 1-C诱导的JUN/ARID 1A复合物调节近端和远端增强子样标签上的染色质可及性。这些发现揭示了MUC 1-C在染色质重塑中的作用，该作用至少部分由JUN/AP-1和ARID 1A/BAF介导，与驱动CSC状态相关。这些发现表明，CRPC和TNBC CSC状态所必需的MUC 1-C激活了一种涉及JUN/AP-1和ARID 1A/BAF的新途径，该途径调节干细胞相关基因增强子的染色质可及性。
The oncogenic MUC1-C protein promotes dedifferentiation of castrate-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) cells. Chromatin remodeling is critical for the cancer stem cell (CSC) state; however, there is no definitive evidence that MUC1-C regulates chromatin accessibility and thereby expression of stemness-associated genes. We demonstrate that MUC1-C drives global changes in chromatin architecture in the dedifferentiation of CRPC and TNBC cells. Our results show that MUC1-C induces differentially accessible regions (DAR) across their genomes, which are significantly associated with differentially expressed genes (DEG). Motif and cistrome analysis further demonstrated MUC1-C–induced DARs align with genes regulated by the JUN/AP-1 family of transcription factors. MUC1-C activates the BAF chromatin remodeling complex, which is recruited by JUN in enhancer selection. In studies of the NOTCH1 gene, which is required for CRPC and TNBC cell self-renewal, we demonstrate that MUC1-C is necessary for (i) occupancy of JUN and ARID1A/BAF, (ii) increases in H3K27ac and H3K4me3 signals, and (iii) opening of chromatin accessibility on a proximal enhancer–like signature. Studies of the EGR1 and LY6E stemness–associated genes further demonstrate that MUC1-C–induced JUN/ARID1A complexes regulate chromatin accessibility on proximal and distal enhancer–like signatures. These findings uncover a role for MUC1-C in chromatin remodeling that is mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state. These findings show that MUC1-C, which is necessary for the CRPC and TNBC CSC state, activates a novel pathway involving JUN/AP-1 and ARID1A/BAF that regulates chromatin accessibility of stemness-associated gene enhancers.