Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells.
Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells.
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DOI：
10.1016/j.canlet.2017.04.040
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发表时间：
2017-08-10
期刊：
影响因子：
9.7
通讯作者：
Jones PA
中科院分区：
文献类型：
--
作者：
Lakshminarasimhan R;Andreu-Vieyra C;Lawrenson K;Duymich CE;Gayther SA;Liang G;Jones PA
染色质重塑AT丰富的互动结构域1A（ARID1A）经常在卵巢透明细胞癌（OCCC）和子宫内膜异位症前体病变突变。在这里，我们表明，敲低ARID1A在永生化的子宫内膜异位症细胞系是足以诱导肿瘤转化的表型变化的指示，证明了更高的效率的锚定非依赖性生长，增加的倾向，坚持胶原蛋白，和更大的能力，入侵基底膜提取物在体外。ARID1A敲低与99个靶基因的表达失调有关，并且在原发性OCCC组织中也观察到许多这些表达变化。此外，通路分析表明这些基因属于与肿瘤发生高度相关的网络，包括整合素和桩蛋白通路。我们证明，ARID1A的下调不会显著改变整体染色质可及性或DNA甲基化，但出乎意料的是，我们发现启动子区域的活性H3K27ac标记强烈增加，而潜在增强子的H3K27ac标记减少。总之，这些数据提供了证据表明，ARID1A突变可能是子宫内膜异位症细胞致癌转化的早期事件，从而导致OCCC。
The chromatin remodeler AT-Rich Interactive Domain 1A (ARID1A) is frequently mutated in ovarian clear cell carcinoma (OCCC) and endometriosis precursor lesions. Here, we show that knocking down ARID1A in an immortalized endometriosis cell line is sufficient to induce phenotypic changes indicative of neoplastic transformation as evidenced by higher efficiency of anchorage-independent growth, increased propensity to adhere to collagen, and greater capacity to invade basement membrane extract in vitro. ARID1A knockdown is associated with expression dysregulation of 99 target genes, and many of these expression changes are also observed in primary OCCC tissues. Further, pathway analysis indicates these genes fall within networks highly relevant to tumorigenesis including integrin and paxillin pathways. We demonstrate that the down-regulation of ARID1A does not markedly alter global chromatin accessibility or DNA methylation but unexpectedly, we find strong increases in the active H3K27ac mark in promoter regions and decreases of H3K27ac at potential enhancers. Taken together, these data provide evidence that ARID1A mutation can be an early stage event in the oncogenic transformation of endometriosis cells giving rise to OCCC.
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