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A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases
BACKGROUND: The chromatin remodeler NAP1L1, which is upregulated in small intestinal neuroendocrine neoplasms (NENs), has been implicated in cell cycle progression. As p57(Kip2) (CDKN1C), a negative regulator of proliferation and a tumor suppressor, is controlled by members of the NAP1 family, we te...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112619/ https://www.ncbi.nlm.nih.gov/pubmed/25071868 http://dx.doi.org/10.1186/1756-8935-7-15 |
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author | Schimmack, Simon Taylor, Andrew Lawrence, Ben Alaimo, Daniele Schmitz-Winnenthal, Hubertus Büchler, Markus W Modlin, Irvin M Kidd, Mark |
author_facet | Schimmack, Simon Taylor, Andrew Lawrence, Ben Alaimo, Daniele Schmitz-Winnenthal, Hubertus Büchler, Markus W Modlin, Irvin M Kidd, Mark |
author_sort | Schimmack, Simon |
collection | PubMed |
description | BACKGROUND: The chromatin remodeler NAP1L1, which is upregulated in small intestinal neuroendocrine neoplasms (NENs), has been implicated in cell cycle progression. As p57(Kip2) (CDKN1C), a negative regulator of proliferation and a tumor suppressor, is controlled by members of the NAP1 family, we tested the hypothesis that NAP1L1 may have a mechanistic role in regulating pancreatic NEN proliferation through regulation of p57(Kip2). RESULTS: NAP1L1 silencing (siRNA and shRNA/lipofectamine approach) decreased proliferation through inhibition of mechanistic (mammalian) target of rapamycin pathway proteins and their phosphorylation (p < 0.05) in the pancreatic neuroendocrine neoplasm cell line BON in vitro (p < 0.0001) and resulted in significantly smaller (p < 0.05) and lighter (p < 0.05) tumors in the orthotopic pancreatic NEN mouse model. Methylation of the p57( Kip2 ) promoter was decreased by NAP1L1 silencing (p < 0.05), and expression of p57(Kip2) (transcript and protein) was upregulated. For methylation of the p57( Kip2 ) promoter, NAP1L1 bound directly to the promoter (−164 to +21, chromatin immunoprecipitation). In 43 pancreatic NEN samples (38 primaries and 5 metastasis), NAP1L1 was over-expressed in metastasis (p < 0.001), expression which was inversely correlated with p57(Kip2) (p < 0.01) on mRNA and protein levels. Menin was not differentially expressed. CONCLUSION: NAP1L1 is over-expressed in pancreatic neuroendocrine neoplasm metastases and epigenetically promotes cell proliferation through regulation of p57( Kip2 ) promoter methylation. |
format | Online Article Text |
id | pubmed-4112619 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41126192014-07-29 A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases Schimmack, Simon Taylor, Andrew Lawrence, Ben Alaimo, Daniele Schmitz-Winnenthal, Hubertus Büchler, Markus W Modlin, Irvin M Kidd, Mark Epigenetics Chromatin Research BACKGROUND: The chromatin remodeler NAP1L1, which is upregulated in small intestinal neuroendocrine neoplasms (NENs), has been implicated in cell cycle progression. As p57(Kip2) (CDKN1C), a negative regulator of proliferation and a tumor suppressor, is controlled by members of the NAP1 family, we tested the hypothesis that NAP1L1 may have a mechanistic role in regulating pancreatic NEN proliferation through regulation of p57(Kip2). RESULTS: NAP1L1 silencing (siRNA and shRNA/lipofectamine approach) decreased proliferation through inhibition of mechanistic (mammalian) target of rapamycin pathway proteins and their phosphorylation (p < 0.05) in the pancreatic neuroendocrine neoplasm cell line BON in vitro (p < 0.0001) and resulted in significantly smaller (p < 0.05) and lighter (p < 0.05) tumors in the orthotopic pancreatic NEN mouse model. Methylation of the p57( Kip2 ) promoter was decreased by NAP1L1 silencing (p < 0.05), and expression of p57(Kip2) (transcript and protein) was upregulated. For methylation of the p57( Kip2 ) promoter, NAP1L1 bound directly to the promoter (−164 to +21, chromatin immunoprecipitation). In 43 pancreatic NEN samples (38 primaries and 5 metastasis), NAP1L1 was over-expressed in metastasis (p < 0.001), expression which was inversely correlated with p57(Kip2) (p < 0.01) on mRNA and protein levels. Menin was not differentially expressed. CONCLUSION: NAP1L1 is over-expressed in pancreatic neuroendocrine neoplasm metastases and epigenetically promotes cell proliferation through regulation of p57( Kip2 ) promoter methylation. BioMed Central 2014-07-21 /pmc/articles/PMC4112619/ /pubmed/25071868 http://dx.doi.org/10.1186/1756-8935-7-15 Text en Copyright © 2014 Schimmack et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Schimmack, Simon Taylor, Andrew Lawrence, Ben Alaimo, Daniele Schmitz-Winnenthal, Hubertus Büchler, Markus W Modlin, Irvin M Kidd, Mark A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
title | A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
title_full | A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
title_fullStr | A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
title_full_unstemmed | A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
title_short | A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
title_sort | mechanistic role for the chromatin modulator, nap1l1, in pancreatic neuroendocrine neoplasm proliferation and metastases |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112619/ https://www.ncbi.nlm.nih.gov/pubmed/25071868 http://dx.doi.org/10.1186/1756-8935-7-15 |
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