The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma.
The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma.
复制标题
作者：
尤因肉瘤是一种侵袭性骨和软组织的恶性肿瘤，影响儿童和年轻人。尤文肉瘤的发病机制是由EWS/Ets融合癌蛋白驱动的，其中EWS/Fli 1是最常见的。我们先前已经表明，EWS/Fli 1调控的microRNA（miR）有助于尤文肉瘤中的促癌程序。在这里，我们表明，miR-22，EWS/Fli 1抑制的miR，是抑制尤文肉瘤克隆形成和锚定非依赖性细胞生长，即使在适度的过表达水平。我们的研究进一步鉴定了H3 K9 me 1/2组蛋白去甲基化酶KDM 3A（JMJD 1A/JHDM 2A）作为一个新的miR-22调控基因。我们发现KDM 3A在尤文肉瘤中过表达，并且其耗尽抑制多种患者来源的细胞系中的克隆形成和锚定非依赖性生长，以及异种移植模型中的肿瘤发生。KDM 3A缺失进一步导致抑制性H3 K9 me 2组蛋白标记水平的增加，以及尤文肉瘤中促癌因子的下调。总之，我们的研究确定了组蛋白去甲基化酶KDM 3A作为一种新的，miR调节的，尤文肉瘤的肿瘤促进剂。
Ewing Sarcoma is a biologically aggressive bone and soft tissue malignancy affecting children and young adults. Ewing Sarcoma pathogenesis is driven by EWS/Ets fusion oncoproteins, of which EWS/Fli1 is the most common. We have previously shown that microRNAs (miRs) regulated by EWS/Fli1 contribute to the pro-oncogenic program in Ewing Sarcoma. Here we show that miR-22, an EWS/Fli1-repressed miR, is inhibitory to Ewing Sarcoma clonogenic and anchorage-independent cell growth, even at modest overexpression levels. Our studies further identify the H3K9me1/2 histone demethylase KDM3A (JMJD1A/JHDM2A) as a new miR-22-regulated gene. We show that KDM3A is overexpressed in Ewing Sarcoma, and that its depletion inhibits clonogenic and anchorage-independent growth in multiple patient-derived cell lines, and tumorigenesis in a xenograft model. KDM3A depletion further results in augmentation of the levels of the repressive H3K9me2 histone mark, and downregulation of pro-oncogenic factors in Ewing Sarcoma. Together, our studies identify the histone demethylase KDM3A as a new, miR-regulated, tumor promoter in Ewing Sarcoma.
登录
查看更多内容
影响因子：
8
作者：
Patel, J. B.;Appaiah, H. N.;Nakshatri, H.
通讯作者：
Nakshatri, H.
影响因子：
--
作者：
Nagaraja, Ankur K.;Creighton, Chad J.;Matzuk, Martin M.
通讯作者：
Matzuk, Martin M.
DOI：
10.1126/science.1198056
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Li M;Zhang X;Jones S;Leary RJ;Lin JC;Boca SM;Carter H;Samayoa J;Bettegowda C;Gallia GL;Jallo GI;Binder ZA;Nikolsky Y;Hartigan J;Smith DR;Gerhard DS;Fults DW;VandenBerg S;Berger MS;Marie SK;Shinjo SM;Clara C;Phillips PC;Minturn JE;Biegel JA;Judkins AR;Resnick AC;Storm PB;Curran T;He Y;Rasheed BA;Friedman HS;Keir ST;McLendon R;Northcott PA;Taylor MD;Burger PC;Riggins GJ;Karchin R;Parmigiani G;Bigner DD;Yan H;Papadopoulos N;Vogelstein B;Kinzler KW;Velculescu VE
通讯作者：
Velculescu VE
影响因子：
5.6
作者：
Gurtan, Allan M.;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.
DOI：
10.1038/nrg3173
发表时间：
2012-04-03
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--