PMID- 30190513 OWN - NLM STAT- MEDLINE DCOM- 20200402 LR - 20201009 IS - 1476-5500 (Electronic) IS - 0929-1903 (Print) IS - 0929-1903 (Linking) VI - 26 IP - 3-4 DP - 2019 Mar TI - Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes beta-cell proliferation. PG - 94-102 LID - 10.1038/s41417-018-0046-x [doi] AB - 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 beta-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet beta-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote beta-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased beta-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 beta-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet beta-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors. FAU - Yuan, Ziqiang AU - Yuan Z AD - Department of Medical Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Gardiner, Juliet C AU - Gardiner JC AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Maggi, Elaine C AU - Maggi EC AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. AD - Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Adem, Asha AU - Adem A AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Zhang, George AU - Zhang G AD - Department of Pathology and Lab Medicine, Weill Cornell Medicine, New York, NY, USA. FAU - Lee, Sylvia AU - Lee S AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Romanienko, Peter AU - Romanienko P AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Du, Yi-Chieh Nancy AU - Du YN AD - Department of Pathology and Lab Medicine, Weill Cornell Medicine, New York, NY, USA. FAU - Libutti, Steven K AU - Libutti SK AD - Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. Steven.libutti@cinj.rutgers.edu. AD - Department of Surgery, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Steven.libutti@cinj.rutgers.edu. LA - eng GR - P50 CA174521/CA/NCI NIH HHS/United States GR - R01 CA170911/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20180907 PL - England TA - Cancer Gene Ther JT - Cancer gene therapy JID - 9432230 RN - 0 (Antineoplastic Agents) RN - 0 (Men1 protein, mouse) RN - 0 (Proto-Oncogene Proteins) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1) RN - EC 2.1.1.37 (Dnmt1 protein, mouse) SB - IM MH - Alpharetrovirus/genetics MH - Animals MH - Antineoplastic Agents/pharmacology/therapeutic use MH - Cell Line, Tumor MH - Cell Proliferation/genetics MH - Chickens MH - DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors/genetics/*metabolism MH - Disease Models, Animal MH - Fibroblasts MH - Gene Transfer Techniques MH - Genetic Vectors/administration & dosage/genetics MH - Humans MH - Islets of Langerhans/metabolism/*pathology MH - Mice MH - Mice, Transgenic MH - Molecular Targeted Therapy/methods MH - Multiple Endocrine Neoplasia Type 1/drug therapy/genetics/*pathology MH - Pancreatic Neoplasms/drug therapy/genetics/*pathology MH - Proto-Oncogene Proteins/genetics MH - Up-Regulation/drug effects/genetics PMC - PMC7540611 MID - NIHMS1634573 COIS- Conflict of interest The authors declare that they have no conflict of interest. EDAT- 2018/09/08 06:00 MHDA- 2020/04/03 06:00 PMCR- 2020/10/07 CRDT- 2018/09/08 06:00 PHST- 2018/04/16 00:00 [received] PHST- 2018/08/05 00:00 [accepted] PHST- 2018/07/31 00:00 [revised] PHST- 2018/09/08 06:00 [pubmed] PHST- 2020/04/03 06:00 [medline] PHST- 2018/09/08 06:00 [entrez] PHST- 2020/10/07 00:00 [pmc-release] AID - 10.1038/s41417-018-0046-x [pii] AID - 10.1038/s41417-018-0046-x [doi] PST - ppublish SO - Cancer Gene Ther. 2019 Mar;26(3-4):94-102. doi: 10.1038/s41417-018-0046-x. Epub 2018 Sep 7.