Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer.
Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer.
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DOI：
10.1038/onc.2009.297
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发表时间：
2009-12-17
期刊：
影响因子：
8
通讯作者：
Yang, Z-Q
中科院分区：
文献类型：
--
作者：
Liu, G.;Bollig-Fischer, A.;Kreike, B.;van de Vijver, M. J.;Abrams, J.;Ethier, S. P.;Yang, Z-Q
此前，通过在食管癌细胞系中定位9p23-24扩增子，我们定位克隆了GASC1（在鳞状细胞癌1中扩增的基因），该基因编码具有Jumonji C （JmjC）结构域的核蛋白，催化组蛋白赖氨酸(K)去甲基化。然而，GASC1在乳腺癌中的转化作用仍有待确定。在这项研究中，我们发现GASC1是乳腺癌，特别是基底样亚型中9p23-24区域的扩增基因之一。与非基底样乳腺癌相比，侵袭性基底样乳腺癌中GASC1转录物的表达水平明显更高。我们的体外实验表明，当GASC1在永生化、非转化的乳腺上皮MCF10A细胞中过表达时，可诱导转化表型，包括生长因子不依赖的增殖、锚定不依赖的生长、Matrigel中形态发生的改变和乳腺球形成能力。此外，GASC1去甲基化酶活性调节干细胞自我更新的关键基因的表达，包括NOTCH1，并可能与乳腺癌中的干细胞表型有关。因此，GASC1是人类乳腺癌9p23-24扩增子中的驱动癌基因，靶向抑制GASC1组蛋白去甲基化酶可能为癌症治疗开发提供潜在的新途径。
Previously, mapping of the 9p23-24 amplicon in esophageal cancer cell lines led us to the positional cloning of GASC1 (gene amplified in squamous cell carcinoma 1), which encodes a nuclear protein with a Jumonji C (JmjC) domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23-24 region in breast cancer, particularly in basal-like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal-like breast cancers compared with non basal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage-independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when over expressed in immortalized, nontransformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
8.8
作者：
Forozan, F;Veldman, R;Ammerman, CA;Parsa, NZ;Kallioniemi, A;Kallioniemi, OP;Ethier, SP
通讯作者：
Ethier, SP
ERBB-2 过表达赋予人乳腺上皮细胞 PI 3' 激酶依赖性侵袭能力。
影响因子：
8.8
作者：
Ignatoski KM;Maehama T;Markwart SM;Dixon JE;Livant DL;Ethier SP
通讯作者：
Ethier SP
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.