BRCA1-Associated Epigenetic Regulation of p73 Mediates an Effector Pathway for Chemosensitivity in Ovarian Carcinoma
BRCA1-Associated Epigenetic Regulation of p73 Mediates an Effector Pathway for Chemosensitivity in Ovarian Carcinoma
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DOI：
10.1158/0008-5472.can-10-0668
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发表时间：
2010-09-15
期刊：
影响因子：
11.2
通讯作者：
Ellisen, Leif W.
中科院分区：
文献类型：
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作者：
Ibrahim, Nageatte;He, Lei;Ellisen, Leif W.
在BRCA1突变携带者中产生的大多数肿瘤表现为p53失活，p53是DNA损伤后细胞死亡的关键效应因子。尽管p53缺失，brca1缺失的肿瘤细胞对顺铂的敏感性增加，brca1相关卵巢癌患者与散发性病例相比，铂基化疗改善了预后。虽然已知brca1相关癌症的化学敏感性与未修复的DNA损伤有关，但在这些肿瘤中，介导铂诱导损伤的细胞反应的特异性效应途径尚不清楚。在这里，我们发现p53相关基因p73通过一种新的表观遗传机制在人类和小鼠brca1相关卵巢癌模型中上调，该基因编码一种在许多情况下与化学敏感性相关的促凋亡蛋白。brca1缺失的卵巢癌细胞在p73调控区域（包括p73转录抑制因子ZEB1的结合位点）内表现出超甲基化，导致ZEB1的结合消失和反活化p73亚型的表达增加（TAp73）。顺铂化疗在brca1缺陷细胞中特异性诱导TAp73靶基因，在这些细胞中敲低TAp73会引起化疗耐药，而对表达brca1的肿瘤细胞几乎没有影响。在原发性卵巢癌中，ZEB1结合位点甲基化和TAp73表达与BRCA1状态和临床反应相关。总之，这些发现揭示了一种新的调节机制，支持TAp73作为卵巢癌亚群铂化疗反应的重要介质的贡献。TAp73可能是提高该疾病化疗敏感性的反应预测因子和潜在的治疗靶点。癌症Res;70 (18);7155 - 65。AACR (C) 2010。
The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death after DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared with sporadic cases. Although it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here, we show that the p53-related gene p73, encoding a proapoptotic protein that is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 might represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease. Cancer Res; 70(18); 7155-65. (C)2010 AACR.