BACKGROUND & AIMS AT-rich interaction domain 1a (Arid1a), a component of the chromatin remodeling complex, has emerged as a tumor suppressor gene. It is frequently mutated in hepatocellular carcinoma (HCC). However, it remains unknown how Arid1a suppresses HCC development and whether Arid1a deficiency could be exploited for therapy, we aimed to explore these questions. METHODS The expression of Arid1a in human and mouse HCCs was determined by immunohistochemical (IHC) staining. Gene expression was determined by quantitative PCR, ELISA or western blotting. Arid1a knockdown HCC cell lines were established by lentiviral-based shRNA. Tumor angiogenesis was quantified based on vessel density. The regulation of angiopoietin (Ang2) expression by Arid1a was identified by chromatin immunoprecipitation (ChIP) assay. The tumor promoting function of Arid1a loss was studied with a xenograft model in nude mice and diethylnitrosamine (DEN)-induced HCC in Arid1a conditional knockout mice. The therapeutic values of Ang2 antibody and sorafenib treatment were evaluated both in vitro and in vivo. RESULTS We demonstrate that Arid1a deficiency, occurring in advanced human HCCs, is associated with increased vessel density. Mechanistically, loss of Arid1a causes aberrant histone H3K27ac deposition at the angiopoietin-2 (Ang2) enhancer and promoter, which eventually leads to ectopic expression of Ang2 and promotes HCC development. Ang2 blockade in Arid1a-deficient HCCs significantly reduces vessel density and tumor progression. Importantly, sorafenib treatment, which suppresses H3K27 acetylation and Ang2 expression, profoundly halts the progression of Arid1a-deficient HCCs. CONCLUSIONS Arid1a-deficiency activates Ang2-dependent angiogenesis and promotes HCC progression. Loss of Arid1a in HCCs confers sensitivity to Ang2 blockade and sorafenib treatment. LAY SUMMARY AT-rich interaction domain 1a (Arid1a), is a tumor suppressor gene. Arid1a-deficiency promotes Ang2-dependent angiogenesis leading to hepatocellular carcinoma progression. Arid1a-deficiency also sensitizes tumors to Ang2 blockade by sorafenib treatment.

中文翻译：

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Arid1a 调节晚期肝细胞癌抗血管生成治疗的反应

背景和目的 富含 AT 的相互作用域 1a (Arid1a) 是染色质重塑复合物的一个组成部分，已成为一种肿瘤抑制基因。它经常在肝细胞癌 (HCC) 中发生突变。然而，Arid1a 如何抑制 HCC 发展以及 Arid1a 缺陷是否可以用于治疗仍然未知，我们旨在探索这些问题。方法 通过免疫组织化学 (IHC) 染色测定 Arid1a 在人和小鼠 HCC 中的表达。通过定量 PCR、ELISA 或蛋白质印迹确定基因表达。Arid1a 敲低 HCC 细胞系是通过基于慢病毒的 shRNA 建立的。基于血管密度量化肿瘤血管生成。Arid1a 对血管生成素 (Ang2) 表达的调节是通过染色质免疫沉淀 (ChIP) 测定确定的。用裸鼠的异种移植模型和二乙基亚硝胺 (DEN) 诱导的 Arid1a 条件敲除小鼠的 HCC 研究了 Arid1a 缺失的肿瘤促进功能。在体外和体内评估了 Ang2 抗体和索拉非尼治疗的治疗价值。结果我们证明，发生在晚期人类 HCC 中的 Arid1a 缺陷与血管密度增加有关。从机制上讲，Arid1a 的缺失会导致组蛋白 H3K27ac 在血管生成素 2 (Ang2) 增强子和启动子处异常沉积，最终导致 Ang2 异位表达并促进 HCC 发展。Arid1a 缺陷型 HCC 中的 Ang2 阻断显着降低了血管密度和肿瘤进展。重要的是，抑制 H3K27 乙酰化和 Ang2 表达的索拉非尼治疗可极大地阻止 Arid1a 缺陷型 HCC 的进展。结论 Arid1a 缺陷激活 Ang2 依赖性血管生成并促进 HCC 进展。HCC 中 Arid1a 的缺失赋予了对 Ang2 阻断剂和索拉非尼治疗的敏感性。概述 富含 AT 的相互作用域 1a (Arid1a)，是一种肿瘤抑制基因。Arid1a 缺陷促进 Ang2 依赖性血管生成，导致肝细胞癌进展。Arid1a 缺陷还会使肿瘤对索拉非尼治疗引起的 Ang2 阻断敏感。