SMARCC2 mediates the regulation of DKK1 by the transcription factor EGR1 through chromatin remodeling to reduce the proliferative capacity of glioblastoma.
SMARCC2 mediates the regulation of DKK1 by the transcription factor EGR1 through chromatin remodeling to reduce the proliferative capacity of glioblastoma.
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SMARCC2通过染色质重塑介导转录因子EGR1对DKK1的调节，降低胶质母细胞瘤的增殖能力
DOI：
10.1038/s41419-022-05439-8
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发表时间：
2022-11-23
影响因子：
9
通讯作者：
Zhou, Qiang
中科院分区：
文献类型：
--
作者：
Li, Chiyang;Wang, Tong;Gu, Junwei;Qi, Songtao;Li, Junjie;Chen, Lei;Wu, Hang;Shi, Linyong;Song, Chong;Li, Hong;Zhu, Liwen;Lu, Yuntao;Zhou, Qiang
Switch/蔗糖非发酵 (SWI/SNF) 复合物在染色质重塑中发挥关键作用。近期研究发现SMARCC2作为复合体基本模块的核心亚基，在其早期组装过程中发挥着关键作用。在这项研究中，我们发现 SMARCC2 通过靶向 DKK1 信号轴来抑制胶质母细胞瘤的进展。与低级别胶质瘤相比，恶性胶质母细胞瘤 (GBM) 中 SMARCC2 的表达较低。 SMARCC2敲除促进胶质母细胞瘤细胞的增殖，而其过表达则表现出相反的效果。从机制上来说，SMARCC2通过动态调节染色质结构并关闭可与转录因子EGR1结合的靶基因DKK1的启动子区域来负向调节转录。 DKK1 敲除通过抑制 PI3K-AKT 通路显着减少胶质母细胞瘤细胞系的增殖。我们还研究了SMARCC2的SWIRM和SANT结构域的功能，发现SWIRM结构域在SMARCC2完整的染色质重塑功能中发挥着更重要的作用。此外，体内研究证实，过表达SMARCC2可以显着抑制裸鼠原位颅内胶质瘤的大小。总的来说，这项研究表明，SMARCC2作为一种肿瘤抑制因子，通过染色质重塑靶向癌基因DKK1的转录来抑制胶质母细胞瘤的增殖，这表明SMARCC2是胶质母细胞瘤潜在有吸引力的治疗靶点。
Switch/sucrose-nonfermenting (SWI/SNF) complexes play a key role in chromatin remodeling. Recent studies have found that SMARCC2, as the core subunit of the fundamental module of the complex, plays a key role in its early assembly. In this study, we found a unique function of SMARCC2 in inhibiting the progression of glioblastoma by targeting the DKK1 signaling axis. Low expression of SMARCC2 is found in malignant glioblastoma (GBM) compared with low-grade gliomas. SMARCC2 knockout promoted the proliferation of glioblastoma cells, while its overexpression showed the opposite effect. Mechanistically, SMARCC2 negatively regulates transcription by dynamically regulating the chromatin structure and closing the promoter region of the target gene DKK1, which can be bound by the transcription factor EGR1. DKK1 knockdown significantly reduced the proliferation of glioblastoma cell lines by inhibiting the PI3K–AKT pathway. We also studied the functions of the SWIRM and SANT domains of SMARCC2 and found that the SWIRM domain plays a more important role in the complete chromatin remodeling function of SMARCC2. In addition, in vivo studies confirmed that overexpression of SMARCC2 could significantly inhibit the size of intracranial gliomas in situ in nude mice. Overall, this study shows that SMARCC2, as a tumor suppressor, inhibits the proliferation of glioblastoma by targeting the transcription of the oncogene DKK1 through chromatin remodeling, indicating that SMARCC2 is a potentially attractive therapeutic target in glioblastoma.
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影响因子：
21.3
作者：
Garry GA;Bezprozvannaya S;Chen K;Zhou H;Hashimoto H;Morales MG;Liu N;Bassel-Duby R;Olson EN
通讯作者：
Olson EN
影响因子：
37.3
作者：
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Xie SQ
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9
作者：
Di M;Wang L;Li M;Zhang Y;Liu X;Zeng R;Wang H;Chen Y;Chen W;Zhang Y;Zhang M
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影响因子：
8.8
作者：
Narayanan, Ramanathan;Pirouz, Mehdi;Tuoc, Tran
通讯作者：
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