A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases

Abstract

BackgroundThe chromatin remodeler NAP1L1, which is upregulated in small intestinal neuroendocrine neoplasms (NENs), has been implicated in cell cycle progression. As p57Kip2 (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 p57Kip2.ResultsNAP1L1 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 p57Kip2 (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 p57Kip2 (p < 0.01) on mRNA and protein levels. Menin was not differentially expressed.ConclusionNAP1L1 is over-expressed in pancreatic neuroendocrine neoplasm metastases and epigenetically promotes cell proliferation through regulation of p57 Kip2 promoter methylation.

PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1

“…NAP1L1 is indicated to be involved in ovarian cancer cell responses to cytotoxic gold compounds . In pancreatic neuroendocrine neoplasms, NAP1L1 promotes tumor cell proliferation and regulates cell entry into the S phase via inhibition of the mTOR pathway and epigenetic regulation of p57 promoter methylation . The potential use of NAP1L1 for differentiation between glioblastoma and lower grade gliomas has also been demonstrated .…”

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

“…Some of these genes have been identified in NETs, e.g. Ki67 and nucleosome assembly protein-like 1 (NAP1L1) as markers of proliferation (Kidd et al 2006, Rindi & Wiedenmann 2011 and mechanistically linked to the epigenome (Schimmack et al 2014). Growth factor expression and signaling is a well-known regulator of NET proliferation (Kidd et al 2005) and signaling pathways (e.g.…”

Hepatitis C Virus NS5A Targets Nucleosome Assembly Protein NAP1L1 To Control the Innate Cellular Response

“…Knockdown of NAP1L1 enhances the differentiation of induced pluripotent stem cells (iPSC) into functional cardiomyocytes (33). NAP1L1 expression has also been shown to be elevated in several cancers (34)(35)(36).…”