State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pathology, Zhejiang Cancer Hospital, Zhejiang, China.
Cancer Res. 2020 Feb 1;80(3):406-417. doi: 10.1158/0008-5472.CAN-18-2446.
Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and is the most frequently mutated component. However, some components of SWI/SNF complexes, including , 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 anti-inflammatory 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.
SWI/SNF 染色质重塑复合物在人类癌症中的突变率约为 20%，是突变最频繁的组件。然而，SWI/SNF 复合物的一些组件，包括 ARID1A，在鳞状细胞癌 (SCC) 中的突变率非常低，其在 SCC 中的作用尚不清楚。在这里，我们证明 SCC 中 ARID1A 的低表达是启动子超甲基化的结果。ARID1A 的低水平与预后不良相关。ARID1A 通过直接和间接的染色质重塑机制维持转录组稳态。ARID1A 的缺失会激活致癌转录组，从而推动 SCC 的进展。具有抗炎作用的天然产物白头翁内酯由于其对 HDAC1 和致癌信号的抑制作用，对 ARID1A 缺失的 SCC 细胞具有合成致死作用。这些发现支持将白头翁内酯应用于治疗 ARID1A 低表达的 SCC 患者的临床应用。
本研究揭示了 ARID1A 在 SCC 中的新型失活机制和肿瘤抑制作用，并提出白头翁内酯可作为治疗 ARID1A 低表达 SCC 患者的有效方法。
