Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells.
Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells.
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DOI：
10.18632/oncotarget.6717
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发表时间：
2016-03-08
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影响因子：
--
通讯作者：
Kleeff J
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文献类型：
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作者：
Benitz S;Regel I;Reinhard T;Popp A;Schäffer I;Raulefs S;Kong B;Esposito I;Michalski CW;Kleeff J
腺泡到导管的化生(ADM)发生在蓝蛋白介导的胰腺炎或致癌的Kras驱动的胰腺癌发展中，伴随着转录程序的广泛变化。在这个过程中，腺泡细胞关闭了腺泡特异性分化基因的表达，并重新表达了通常在胚胎胰腺前体细胞中发现的基因。先前的研究已经证明，腺泡特异性转录因子的缺失会使细胞对致癌转化敏感，最终导致癌症的发生。然而，腺泡细胞命运基因在ADM和胰腺癌中转录沉默的机制在很大程度上是未知的。在这里，我们分析了ADMS和肿瘤细胞中多梳状抑制物复合体1(PRC1)成分Bmi1和Ring1b及其催化的组蛋白修饰H2AK119ub水平的升高是否与腺泡细胞基因沉默有关。因此，我们在体外产生的ADMS和分离的小鼠肿瘤细胞中进行了染色质免疫沉淀，以对抗抑制性组蛋白修饰H3K27me3和H2AK119ub。我们证实腺泡转录因子复合体PTF1-L在ADMS和胰腺肿瘤细胞中是表观遗传沉默的。这项工作首次提出了腺泡细胞基因沉默的可能机制，这是启动和维持ADMS和肿瘤细胞去分化细胞状态的重要前提。
Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells.