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DNMT1 Inhibition Reprograms Pancreatic Cancer Stem Cells via Upregulation of the miR-17-92 Cluster

Title: DNMT1 Inhibition Reprograms Pancreatic Cancer Stem Cells via Upregulation of the miR-17-92 Cluster
Authors: Zagorac, S
Alcala, S
Fernandez Bayon, G
Bou Kheir, T
Schoenhals, M
González-Neira, A
Fernandez Fraga, M
Aicher, A
Heeschen, C
Sainz, B
Item Type: Journal Article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, with cancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression, metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile of PDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance and tumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC. Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenic potential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSC biology and also provide a rationale to develop epigenetic modulators to target CSC plasticity and improve the poor outcome of PDAC patients. Cancer Res; 76(15); 1-13. ©2016 AACR.
Issue Date: 3-Jun-2016
Date of Acceptance: 27-Apr-2016
URI: http://hdl.handle.net/10044/1/38924
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-15-3268
ISSN: 1538-7445
Publisher: American Association for Cancer Research
Start Page: 4546
End Page: 4558
Journal / Book Title: Cancer Research
Volume: 76
Issue: 15
Copyright Statement: © 2016 American Association for Cancer Research.
Keywords: Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status: Published
Open Access location: http://qmro.qmul.ac.uk/xmlui/handle/123456789/13464
Appears in Collections:Division of Cancer



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