ARID1A loss activates MAPK signaling via DUSP4 downregulation.
ARID1A loss activates MAPK signaling via DUSP4 downregulation.
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DOI：
10.1186/s12929-023-00985-5
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发表时间：
2023-12-09
影响因子：
11
通讯作者：
中科院分区：
文献类型：
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作者：
ARID 1A是一种编码BAF 250（一种参与染色质重塑的蛋白质）的肿瘤抑制基因，在子宫内膜相关恶性肿瘤（包括卵巢或子宫透明细胞癌（CCC）和子宫内膜样癌（EMCA））中经常发生突变。然而，ARID 1A突变如何改变下游信号以促进肿瘤发展尚未确定。我们使用RNA测序（RNA-seq）来探索删除ARID 1A后同基因人类子宫内膜上皮细胞的转录组学变化。染色质免疫沉淀测序（ChIP-seq）用于评估DUSP 4启动子和调控区上的活性或抑制性组蛋白标记。我们使用基因工程小鼠子宫内膜样癌模型、人子宫内膜样癌组织和计算机模拟方法验证了我们的发现。RNA-seq揭示了MAPK磷酸酶双特异性磷酸酶4（DUSP 4）在ARID 1A缺陷细胞中的下调。ChIP-seq证明DUSP 4调控区上的组蛋白乙酰化标记（H3 K27 Ac、H3 K9 Ac）减少是ARID 1A缺陷细胞中DUSP 4下调的原因之一。异位DUSP 4表达降低了细胞增殖，并且抑制MAPK通路的DUSP 4显著减轻了体内肿瘤形成。我们的研究结果表明，ARID 1A蛋白通过重塑染色质转录调节DUSP 4的表达，随后使MAPK通路失活，导致肿瘤抑制。ARID 1A-DUSP 4-MAPK轴可以进一步考虑用于开发针对ARID 1A突变癌症的靶向疗法。在线版本包含补充材料，可通过10.1186/s12929-023-00985-5获得。
ARID1A, a tumor suppressor gene encoding BAF250, a protein participating in chromatin remodeling, is frequently mutated in endometrium-related malignancies, including ovarian or uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). However, how ARID1A mutations alter downstream signaling to promote tumor development is yet to be established. We used RNA-sequencing (RNA-seq) to explore transcriptomic changes in isogenic human endometrial epithelial cells after deleting ARID1A. Chromatin immunoprecipitation sequencing (ChIP-seq) was employed to assess the active or repressive histone marks on DUSP4 promoter and regulatory regions. We validated our findings using genetically engineered murine endometroid carcinoma models, human endometroid carcinoma tissues, and in silico approaches. RNA-seq revealed the downregulation of the MAPK phosphatase dual-specificity phosphatase 4 (DUSP4) in ARID1A-deficient cells. ChIP-seq demonstrated decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 regulatory regions as one of the causes for DUSP4 downregulation in ARID1A-deficient cells. Ectopic DUSP4 expression decreased cell proliferation, and pharmacologically inhibiting the MAPK pathway significantly mitigated tumor formation in vivo. Our findings suggest that ARID1A protein transcriptionally modulates DUSP4 expression by remodeling chromatin, subsequently inactivating the MAPK pathway, leading to tumor suppression. The ARID1A-DUSP4-MAPK axis may be further considered for developing targeted therapies against ARID1A-mutated cancers. The online version contains supplementary material available at 10.1186/s12929-023-00985-5.
DOI：
10.3390/diagnostics11101939
发表时间：
2021-10-19
期刊：
Diagnostics (Basel, Switzerland)
影响因子：
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作者：
Bang S;Jee S;Son H;Wi YC;Kim H;Park H;Myung J;Shin SJ;Paik SS
通讯作者：
Paik SS