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Cancer Gene Ther. 2019 Mar;26(3-4):94-102. doi: 10.1038/s41417-018-0046-x. Epub 2018 Sep 7.

Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation.

Author information

1
Department of Medical Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
2
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
3
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
4
Department of Pathology and Lab Medicine, Weill Cornell Medicine, New York, NY, USA.
5
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. Steven.libutti@cinj.rutgers.edu.
6
Department of Surgery, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Steven.libutti@cinj.rutgers.edu.

Abstract

We reported that inactivation of menin (the protein product of MEN1) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased β-cell proliferation. In vivo, our results showed that the levels of serum insulin were increased in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Furthermore, we confirmed that mRNA and protein expression of Dnmt1 as well as Dnmt1 enzyme activity were upregulated in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Finally, we demonstrated that upregulation of Dnmt1 resulted in hyperplasia through β-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet β-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors.

PMID:
30190513
DOI:
10.1038/s41417-018-0046-x

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