NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells.
NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells.
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DOI：
10.1158/0008-5472.can-13-2733
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发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Tsichlis PN
中科院分区：
文献类型：
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作者：
Kottakis F;Foltopoulou P;Sanidas I;Keller P;Wronski A;Dake BT;Ezell SA;Shen Z;Naber SP;Hinds PW;McNiel E;Kuperwasser C;Tsichlis PN
JmjC结构域组蛋白H3 K36 me 2/me 1去甲基化酶NDY 1/KDM 2B在各种类型的癌症中过表达。在这里，我们表明，敲低NDY 1在一组10个细胞系来自广泛的人类肿瘤抑制其锚定依赖性和锚定非依赖性的生长诱导衰老和/或凋亡的一些和抑制G1期进展。我们进一步表明，在乳腺癌细胞系中敲低NDY 1降低了乳腺球的数量、大小和再铺板效率，下调了干细胞标志物ALDH和CD 44，同时上调了CD 24。这些发现结合起来，表明NDY 1是癌症干细胞自我更新所必需的，并且与其他发现一致，这些发现表明，在动物中原位注射后，NDY 1被敲低的肿瘤细胞经历分化，并且需要更多数量的肿瘤细胞来诱导乳腺癌。在机制上，NDY 1作为一组靶向多梳复合物PRC 1和PRC 2的几个成员的microRNA的主调节因子发挥作用，并且其敲低导致这些microRNA的去抑制和它们的多梳靶的下调。与这些观察结果一致，NDY 1/KDM 2B在基底样三阴性乳腺癌中以较高水平表达，并且其过表达与治疗后较高的复发率相关。此外，NDY 1调节的microRNA在正常和癌症乳腺干细胞中均下调。最后，在原发性人类乳腺癌中，NDY 1/KDM 2B表达与NDY 1调节的microRNA的表达呈负相关，与其PRC靶点的表达呈正相关。
The JmjC domain histone H3K36me2/me1 demethylase NDY1/KDM2B is overexpressed in various types of cancer. Here we show that knocking down NDY1 in a set of ten cell lines derived from a broad range of human tumors inhibited their anchorage-dependent and anchorage-independent growth by inducing senescence and/or apoptosis in some and by inhibiting G1 progression in all. We further show that the knockdown of NDY1 in mammary adenocarcinoma cell lines decreased the number, size and replating efficiency of mammospheres and downregulated the stem cell markers ALDH and CD44, while upregulating CD24. These findings combined, suggest that NDY1 is required for the self-renewal of cancer stem cells and are in agreement with additional findings showing that, tumor cells in which NDY1 was knocked down undergo differentiation and a higher number of them is required to induce mammary adenocarcinomas, upon orthotopic injection in animals. Mechanistically, NDY1 functions as a master regulator of a set of microRNAs that target several members of the polycomb complexes PRC1 and PRC2 and its knockdown results in the de-repression of these microRNAs and the downregulation of their polycomb targets. Consistent with these observations, NDY1/KDM2B is expressed at higher levels in basal-like triple negative breast cancers and its overexpression is associated with higher rates of relapse after treatment. In addition, NDY1-regulated microRNAs are downregulated in both normal and cancer mammary stem cells. Finally, in primary human breast cancer, NDY1/KDM2B expression correlates negatively with the expression of the NDY1-regulated microRNAs, and positively with the expression of their PRC targets.