Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
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DOI：
10.1371/journal.pgen.1009708
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发表时间：
2021-07
期刊：
影响因子：
4.5
通讯作者：
Hollenhorst PC
中科院分区：
文献类型：
--
作者：
Strittmatter BG;Jerde TJ;Hollenhorst PC
TMPRSS 2/ERG基因重排发生在50%的前列腺肿瘤中，并导致转录因子ERG的表达，而该转录因子ERG通常在前列腺细胞中沉默。当与PI 3 K/AKT通路激活结合时，ERG表达促进前列腺肿瘤形成和管腔上皮细胞命运，然而协同作用的机制尚不清楚。与管腔命运相反，在永生化的正常前列腺上皮细胞中单独表达ERG促进细胞迁移和上皮向间质转化（EMT）。迁移需要通过内源性Ras/ERK信号传导的ERG丝氨酸96磷酸化。我们发现，一个磷酸化模拟突变体，S96 E ERG，驱动肿瘤形成和克隆生存没有激活AKT。S96仅在核ERG上磷酸化，并且ERK差异募集到与ERG激活相关的ERG结合染色质的子集，但不与ERG抑制基因相关。S96 E不改变ERG基因组结合，但引起ERG介导的抑制、EZH 2结合和H3 K27甲基化的丧失。相反，AKT激活改变了ERG顺反组，并促进了管腔细胞命运基因的表达。这些数据表明，根据AKT状态，ERG可以促进管腔或EMT转录程序，但ERG可以促进肿瘤发生，而不依赖于这些细胞的命运，肿瘤发生只需要转录激活功能。ERG是前列腺癌中最常见的癌基因。ERG蛋白可以结合DNA，激活某些基因并抑制其他基因。先前的研究表明，ERG本身不能促进癌症，但ERG与激活蛋白质AKT的突变共同作用。在这项研究中，我们发现AKT的激活改变了ERG调节的基因，导致管腔上皮分化，这是大多数前列腺肿瘤的标志。然而，我们还发现，一种可以激活但不能抑制基因的突变型ERG可以在不激活AKT的情况下驱动前列腺肿瘤发生，但这种突变型ERG不能促进管腔分化。我们的研究结果表明，视网膜电图介导的肿瘤发生只需要视网膜电图的激活功能，可以发生独立的管腔细胞分化。
The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function. ERG is the most common oncogene in prostate cancer. The ERG protein can bind DNA and can activate some genes and repress others. Previous studies indicated that ERG cannot promote cancer by itself, but that ERG works together with mutations that activate the protein AKT. In this study we found that activation of AKT changes the genes that ERG regulates, leading to luminal epithelial differentiation, which is a hallmark of most prostate tumors. However, we also found that a mutant version of ERG that can activate, but cannot repress genes, can drive prostate tumorigenesis without activation of AKT, but this mutant ERG cannot promote luminal differentiation. Our findings suggest that ERG mediated tumorigenesis only requires ERG’s activation function and can occur independent of luminal cell differentiation.
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影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
DOI：
10.1126/science.1189992
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Goldstein AS;Huang J;Guo C;Garraway IP;Witte ON
通讯作者：
Witte ON
DOI：
10.1158/1078-0432.ccr-18-0653
发表时间：
2018-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Blee AM;He Y;Yang Y;Ye Z;Yan Y;Pan Y;Ma T;Dugdale J;Kuehn E;Kohli M;Jimenez R;Chen Y;Xu W;Wang L;Huang H
通讯作者：
Huang H
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
2.9
作者：
Adamo, Patricia;Porazinski, Sean;Ladomery, Michael R.
通讯作者：
Ladomery, Michael R.