Targeting Zfp148 activates p53 and reduces tumor initiation in the gut.
Targeting Zfp148 activates p53 and reduces tumor initiation in the gut.
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DOI：
10.18632/oncotarget.10899
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发表时间：
2016-08-30
期刊：
影响因子：
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通讯作者：
Lindahl P
中科院分区：
文献类型：
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作者：
Nilton A;Sayin VI;Zou ZV;Sayin SI;Bondjers C;Gul N;Agren P;Fogelstrand P;Nilsson O;Bergo MO;Lindahl P
转录因子锌指蛋白148 （Zfp148, ZBP-89， BFCOL, BERF1, htβ）与肿瘤抑制因子p53相互作用，但这种相互作用的意义尚不清楚。我们最近发现，敲除小鼠的Zfp148会导致一些组织和培养成纤维细胞中p53的异位激活，这表明Zfp148抑制了p53的活性。在这里，我们假设靶向Zfp148可以释放p53活性并防止癌症发展，并在APCMin/+肠腺瘤小鼠模型中验证了这一想法。丢失一个Zfp148拷贝可显著减少肿瘤数量和肿瘤相关肠出血，并提高生存率。此外，在结直肠癌启动事件β-catenin激活后，zfp148缺陷激活了APCMin/+小鼠肠外植体中的p53并诱导凋亡。靶向Zfp148的抗肿瘤作用依赖于p53，因为在缺乏一个或两个Trp53拷贝的APCMin/+小鼠中，缺乏Zfp148并不影响肿瘤数量。结果表明，Zfp148通过抑制p53来控制新转化的肠道肿瘤细胞的命运，靶向Zfp148可能有助于治疗结直肠癌。
The transcription factor Zinc finger protein 148 (Zfp148, ZBP-89, BFCOL, BERF1, htβ) interacts physically with the tumor suppressor p53, but the significance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in some tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesize that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas. Loss of one copy of Zfp148 markedly reduced tumor numbers and tumor-associated intestinal bleedings, and improved survival. Furthermore, after activation of β-catenin-the initiating event in colorectal cancer-Zfp148 deficiency activated p53 and induced apoptosis in intestinal explants of APCMin/+ mice. The anti-tumor effect of targeting Zfp148 depended on p53, as Zfp148 deficiency did not affect tumor numbers in APCMin/+ mice lacking one or both copies of Trp53. The results suggest that Zfp148 controls the fate of newly transformed intestinal tumor cells by repressing p53 and that targeting Zfp148 might be useful in the treatment of colorectal cancer.