Human ex vivo prostate tissue model system identifies ING3 as an oncoprotein.
Human ex vivo prostate tissue model system identifies ING3 as an oncoprotein.
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DOI：
10.1038/bjc.2017.447
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发表时间：
2018-03-06
影响因子：
8.8
通讯作者：
Binda O
中科院分区：
文献类型：
--
作者：
McClurg UL;Nabbi A;Ricordel C;Korolchuk S;McCracken S;Heer R;Wilson L;Butler LM;Irving-Hooper BK;Pedeux R;Robson CN;Riabowol KT;Binda O
尽管在动物模型中，组蛋白标记读取器的生长抑制剂（INhibitor of Growth， ING）家族的创始成员ING1和ING2被定义为肿瘤抑制因子，但其他ING蛋白在细胞增殖和癌症进展中的作用尚不清楚。我们用可诱导的慢病毒颗粒转导体外良性前列腺增生组织表达ING蛋白。H3S10phos免疫组化（IHC）检测细胞增殖情况。在人前列腺癌组织微阵列（TMA）上通过免疫组化（IHC）检测ING3的表达。采用DNA芯片检测基因表达，实时荧光定量pcr验证基因表达。我们发现ING3刺激离体组织的细胞增殖，提示ING3可能致癌。确实，ING3过表达转化了正常的人真皮成纤维细胞。我们观察到前列腺癌样本中ING3水平升高，这与较差的患者生存率相关。与致癌作用一致，基因沉默实验显示，ING3是乳腺癌、卵巢癌和前列腺癌细胞增殖所必需的。最后，ING3通过与染色质修饰因子和转录起始位点的H3K4me3标记相关联，控制了一个复杂的细胞周期基因网络的表达。我们的研究改变了ING蛋白是肿瘤抑制因子的主流观点，并将ING3重新定义为癌蛋白。
Although the founding members of the INhibitor of Growth (ING) family of histone mark readers, ING1 and ING2, were defined as tumour suppressors in animal models, the role of other ING proteins in cellular proliferation and cancer progression is unclear. We transduced ex vivo benign prostate hyperplasia tissues with inducible lentiviral particles to express ING proteins. Proliferation was assessed by H3S10phos immunohistochemistry (IHC). The expression of ING3 was assessed by IHC on a human prostate cancer tissue microarray (TMA). Gene expression was measured by DNA microarray and validated by real-time qPCR. We found that ING3 stimulates cellular proliferation in ex vivo tissues, suggesting that ING3 could be oncogenic. Indeed, ING3 overexpression transformed normal human dermal fibroblasts. We observed elevated levels of ING3 in prostate cancer samples, which correlated with poorer patient survival. Consistent with an oncogenic role, gene-silencing experiments revealed that ING3 is required for the proliferation of breast, ovarian, and prostate cancer cells. Finally, ING3 controls the expression of an intricate network of cell cycle genes by associating with chromatin modifiers and the H3K4me3 mark at transcriptional start sites. Our investigations create a shift in the prevailing view that ING proteins are tumour suppressors and redefine ING3 as an oncoprotein.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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