文章：

INPP4B在正常前列腺及原发性前列腺癌中对EZH2表达的调控作用

Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer

原文发布日期：15 November 2023

DOI: 10.3390/cancers15225418

类型: Article

开放获取: 是

英文摘要：

The phosphatases INPP4B and PTEN are tumor suppressors that are lost in nearly half of advanced metastatic cancers. The loss of PTEN in prostate epithelium initially leads to an upregulation of several tumor suppressors that slow the progression of prostate cancer in mouse models. We tested whether the loss of INPP4B elicits a similar compensatory response in prostate tissue and whether this response is distinct from the one caused by the loss of PTEN. Knockdown of INPP4B but not PTEN in human prostate cancer cell lines caused a decrease in EZH2 expression. InInpp4b−/−mouse prostate epithelium, EZH2 levels were decreased, as were methylation levels of histone H3. In contrast,Ezh2levels were increased in the prostates ofPten−/−male mice. Contrary to PTEN, there was a positive correlation between INPP4B and EZH2 expression in normal human prostates and early-stage prostate tumors. Analysis of single-cell transcriptomic data demonstrated that a subset of EZH2-positive cells expresses INPP4B or PTEN, but rarely both, consistent with their opposing correlation with EZH2 expression. Unlike PTEN, INPP4B did not affect the levels of SMAD4 protein expression orPmlmRNA expression. Like PTEN, p53 protein expression and phosphorylation of Akt inInpp4b−/−murine prostates were elevated. Taken together, the loss of INPP4B in the prostate leads to overlapping and distinct changes in tumor suppressor and oncogenic downstream signaling.

摘要翻译： 

磷酸酶INPP4B与PTEN作为肿瘤抑制因子，在近半数晚期转移性癌症中发生缺失。在前列腺上皮细胞中PTEN的缺失最初会引发多种肿瘤抑制因子的上调，从而在小鼠模型中延缓前列腺癌的进展。本研究旨在探究INPP4B缺失是否会在前列腺组织中引发类似的代偿性反应，以及该反应是否与PTEN缺失引发的反应存在差异。在人前列腺癌细胞系中敲低INPP4B（而非PTEN）导致EZH2表达下降。在Inpp4b−/−小鼠前列腺上皮中，EZH2水平及组蛋白H3甲基化水平均降低；与之相反，Pten−/−雄性小鼠前列腺中Ezh2水平升高。与PTEN不同，在正常人前列腺组织及早期前列腺肿瘤中，INPP4B与EZH2表达呈正相关。单细胞转录组数据分析显示，部分EZH2阳性细胞表达INPP4B或PTEN，但极少同时表达两者，这与它们和EZH2表达的相关性差异相一致。与PTEN不同，INPP4B不影响SMAD4蛋白表达或Pml mRNA表达水平。与PTEN相似的是，Inpp4b−/−小鼠前列腺中p53蛋白表达及Akt磷酸化水平均升高。综上所述，前列腺中INPP4B的缺失会导致肿瘤抑制因子与致癌下游信号通路发生部分重叠且具有特异性的改变。

原文链接：

Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer