Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer.
Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer.
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DOI：
10.3390/cancers15225418
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发表时间：
2023-11-15
期刊：
影响因子：
5.2
通讯作者：
Agoulnik, Irina U.
中科院分区：
文献类型：
--
作者：
Zhang, Manqi;Ceyhan, Yasemin;Mei, Shenglin;Hirz, Taghreed;Sykes, David B.;Agoulnik, Irina U.
前列腺癌是由多种遗传改变驱动的异质性疾病：肿瘤抑制因子的缺失或下调以及癌基因的激活或扩增。前列腺癌中最常见的肿瘤抑制因子是INPP 4 B和PTEN。我们表明，这些蛋白质的损失触发不同的补偿机制，必须克服的进展，从惰性到前列腺癌的晚期。磷酸酶INPP 4 B和PTEN是肿瘤抑制因子，在近一半的晚期转移性癌症中丢失。前列腺上皮中PTEN的缺失最初导致几种肿瘤抑制因子的上调，这些肿瘤抑制因子减缓了小鼠模型中前列腺癌的进展。我们测试了INPP 4 B的缺失是否在前列腺组织中引起类似的代偿反应，以及这种反应是否与PTEN缺失引起的反应不同。在人前列腺癌细胞系中敲低INPP 4 B而非PTEN导致EZH 2表达降低。在Inpp 4 b −/−小鼠前列腺上皮中，EZH 2水平降低，组蛋白H3的甲基化水平也降低。相比之下，Pten−/−雄性小鼠前列腺中的Ezh 2水平增加。与PTEN相反，INPP 4 B和EZH 2在正常人前列腺和早期前列腺肿瘤中的表达呈正相关。单细胞转录组学数据的分析表明，EZH 2阳性细胞的子集表达INPP 4 B或PTEN，但很少同时表达，这与它们与EZH 2表达的相反相关性一致。与PTEN不同，INPP 4 B不影响SMAD 4蛋白表达或Pml mRNA表达水平。与PTEN一样，Inpp 4 b −/−鼠前列腺中p53蛋白表达和Akt磷酸化水平升高。总之，前列腺中INPP 4 B的丢失导致肿瘤抑制和致癌下游信号传导的重叠和不同的变化。
Prostate cancer is a heterogeneous disease driven by multiple genetic alterations: the deletion or downregulation of tumor suppressors and the activation or amplification of oncogenes. Among the most frequently deleted tumor suppressors in prostate cancer are INPP4B and PTEN. We show that the loss of these proteins triggers distinct compensatory mechanisms that must be overcome for the progression from indolent to advanced stages of prostate cancer. 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. In Inpp4b−/− mouse prostate epithelium, EZH2 levels were decreased, as were methylation levels of histone H3. In contrast, Ezh2 levels were increased in the prostates of Pten−/− 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 or Pml mRNA expression. Like PTEN, p53 protein expression and phosphorylation of Akt in Inpp4b−/− 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.
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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
通讯作者：
Schultz N
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
11.2
作者：
Ding L;Chen S;Liu P;Pan Y;Zhong J;Regan KM;Wang L;Yu C;Rizzardi A;Cheng L;Zhang J;Schmechel SC;Cheville JC;Van Deursen J;Tindall DJ;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
DOI：
10.1073/pnas.1411446111
发表时间：
2014-07-29
影响因子：
11.1
作者：
Hieronymus, Haley;Schultz, Nikolaus;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.