Alternative polyadenylation of ZEB1 promotes its translation during genotoxic stress in pancreatic cancer cells.
Alternative polyadenylation of ZEB1 promotes its translation during genotoxic stress in pancreatic cancer cells.
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Zeb1的替代聚腺苷酸化促进了胰腺癌细胞中遗传毒性应激期间的翻译。
DOI：
10.1038/cddis.2017.562
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发表时间：
2017-11-09
影响因子：
9
通讯作者：
Sette C
中科院分区：
文献类型：
--
作者：
Passacantilli I;Panzeri V;Bielli P;Farini D;Pilozzi E;Fave GD;Capurso G;Sette C
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. The standard chemotherapeutic drug, gemcitabine, does not offer significant improvements for PDAC management due to the rapid acquisition of drug resistance by patients. Recent evidence indicates that epithelial-to-mesenchymal transition (EMT) of PDAC cells is strictly associated to early metastasization and resistance to chemotherapy. However, it is not exactly clear how EMT is related to drug resistance or how chemotherapy influences EMT. Herein, we found that ZEB1 is the only EMT-related transcription factor that clearly segregates mesenchymal and epithelial PDAC cell lines. Gemcitabine treatment caused upregulation of ZEB1 protein through post-transcriptional mechanisms in mesenchymal PDAC cells within a context of global inhibition of protein synthesis. The increase in ZEB1 protein correlates with alternative polyadenylation of the transcript, leading to shortening of the 3' untranslated region (UTR) and deletion of binding sites for repressive microRNAs. Polysome profiling indicated that shorter ZEB1 transcripts are specifically retained on the polysomes of PDAC cells during genotoxic stress, while most mRNAs, including longer ZEB1 transcripts, are depleted. Thus, our findings uncover a novel layer of ZEB1 regulation through 3'-end shortening of its transcript and selective association with polysomes under genotoxic stress, strongly suggesting that PDAC cells rely on upregulation of ZEB1 protein expression to withstand hostile environments.
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影响因子：
11.2
作者：
Wang Z;Li Y;Kong D;Banerjee S;Ahmad A;Azmi AS;Ali S;Abbruzzese JL;Gallick GE;Sarkar FH
通讯作者：
Sarkar FH
影响因子：
5.5
作者：
Shkreta L;Chabot B
通讯作者：
Chabot B
影响因子：
21.3
作者：
Wellner, Ulrich;Schubert, Joerg;Brabletz, Thomas
通讯作者：
Brabletz, Thomas
影响因子：
--
作者：
Yu, Lijian;Rege, Mayuri;Volkert, Michael R.
通讯作者：
Volkert, Michael R.
EMT和Stemness：通过在发育和癌症进展方面的替代剪接调整的灵活过程。
影响因子：
37.3
作者：
Pradella D;Naro C;Sette C;Ghigna C
通讯作者：
Ghigna C