The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis.
The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis.
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DOI：
10.1186/1476-4598-13-189
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发表时间：
2014-08-12
期刊：
影响因子：
37.3
通讯作者：
Yen ML
中科院分区：
文献类型：
--
作者：
Hua KT;Wang MY;Chen MW;Wei LH;Chen CK;Ko CH;Jeng YM;Sung PL;Jan YH;Hsiao M;Kuo ML;Yen ML
卵巢癌（OCa）腹膜转移是女性癌症相关死亡的主要原因，可用于治疗的治疗选择有限且预后不良，因为其潜在机制尚未完全了解。在卵巢癌患者的肿瘤标本中评估G9 a表达的临床病理学相关性。分析了卵巢癌细胞系中G9 a的敲低或过表达对粘附、迁移、侵袭和抗失巢凋亡的影响。通过腹膜内异种移植卵巢癌模型测试G9 a的体内生物学功能。基因芯片和定量RT-PCR分析G9 a调控的下游靶基因。我们发现组蛋白甲基转移酶G9 a的表达与晚期、高级别和浆液性OCa高度相关。卵巢癌患者中G9 a表达越高，生存期越短。此外，G9 a在转移性病变中的表达高于其相应的卵巢原发性肿瘤。G9 a表达的下调抑制了卵巢癌细胞系的促转移细胞活性，包括粘附、迁移、侵袭和抗失巢凋亡，而G9 a过表达促进了这些细胞特性。在腹膜播散模型中，G9 a耗竭显著减弱腹水和肿瘤结节的发展。重要的是，微阵列和定量RT-PCR分析显示，G9 a调节卵巢癌中的一组肿瘤抑制基因，包括CDH 1，DUSP 5，SPRY 4和PPP 1 R15 A。这些基因的表达也与OCa标本中G9 a的表达呈负相关。我们认为G9 a有助于卵巢癌转移的多个步骤，并代表了对抗这种致命疾病的新靶点。本文的在线版本（doi：10.1186/1476-4598-13-189）包含补充材料，可供授权用户使用。
Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer–related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease. The online version of this article (doi:10.1186/1476-4598-13-189) contains supplementary material, which is available to authorized users.
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