ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression
ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression
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DOI：
10.1158/0008-5472.can-18-2446
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发表时间：
2020-02-01
期刊：
影响因子：
11.2
通讯作者：
Liu, Zhihua
中科院分区：
文献类型：
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作者：
Luo, Qingyu;Wu, Xiaowei;Liu, Zhihua
Switch/蔗糖不可发酵 (SWI/SNF) 染色质重塑复合物在人类癌症中的突变率约为 20%，ARID1A 是最常见的突变成分。然而，SWI/SNF 复合物的一些成分，包括 ARID1A，在鳞状细胞癌 (SCC) 中表现出非常低的突变率，并且它们在 SCC 中的作用仍不清楚。在这里，我们证明 ARID1A 在 SCC 中的低表达是启动子高甲基化的结果。 ARID1A 水平低与预后不良相关。 ARID1A 通过直接和间接染色质重塑机制维持转录稳态。 ARID1A 的耗竭激活了致癌转录组，从而驱动鳞状细胞癌的进展。抗炎天然产物小白菊内酯由于抑制 HDAC1 和致癌信号传导，对 ARID1A 耗尽的 SCC 细胞具有合成致死作用。这些结果支持了小白菊内酯在治疗低ARID1A表达的鳞状细胞癌患者中的临床应用。意义：本研究揭示了ARID1A在鳞状细胞癌中的新失活机制和抑癌作用，并提出小白菊内酯可作为低ARID1A表达的鳞状细胞癌患者的有效治疗方法。
Switch/Sucrose Non-Fermentable (SWI/SNF) chromatinre-modeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The antiinflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression.Significance: This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.