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NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells.

ABSTRACT: The nucleophosmin (NPM1) activates cancer development and progression in many malignant tumors. However, the regulatory role and underlying mechanisms of NPM1 in pancreatic cancer are unknown. In this study, we showed that NPM1 was up-regulated in PDAC, which indicated a poor prognosis. We also identified NPM1 could stimulate aerobic glycolysis and repress fructose-1, 6-bisphosphatase 1 (FBP1) in pancreatic cancer cells. Restoring FBP1 expression partially reversed the tumor-promoting effects of NPM1, while the loss of FBP1 in PDAC tissues was indicative of a poorer prognosis. In sum, NPM1 promotes aerobic glycolysis and tumor progression in patients with pancreatic cancer by inhibiting FBP1.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC4673277 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells.

Zhu Yi Y Shi Minmin M Chen Hao H Gu Jiangning J Zhang Jiaqiang J Shen Baiyong B Deng Xiaxing X Xie Junjie J Zhan Xi X Peng Chenghong C

Oncotarget 20150801 25

The nucleophosmin (NPM1) activates cancer development and progression in many malignant tumors. However, the regulatory role and underlying mechanisms of NPM1 in pancreatic cancer are unknown. In this study, we showed that NPM1 was up-regulated in PDAC, which indicated a poor prognosis. We also identified NPM1 could stimulate aerobic glycolysis and repress fructose-1, 6-bisphosphatase 1 (FBP1) in pancreatic cancer cells. Restoring FBP1 expression partially reversed the tumor-promoting effects of ...[more]

PMID: 26068981

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Project description:ObjectivePancreatic β cell failure plays a central role in the development of type 2 diabetes (T2D). While the transcription factors shaping the β cell gene expression program have received much attention, the post-transcriptional controls that are activated in β cells during stress are largely unknown. We recently identified JUND as a pro-oxidant transcription factor that is post-transcriptionally upregulated in β cells during metabolic stress. Here we seek to uncover the mechanisms underlying this maladaptive response to metabolic stress.MethodsRNA-protein and protein-protein interactions were measured using RNA immunoprecipitation and co-immunoprecipitation, respectively, in Min6 cells and mouse islets. Phos-tag analyses were used to assess hnRNPK phosphorylation in primary mouse and human islets and Min6 cells. Translating ribosome affinity purification (TRAP) followed by RT-qPCR was used to identify changes in the ribosome occupancy of mRNAs in Min6 cells. Gene depletion studies used lentiviral delivery of CRISPR-Cas9 to Min6 cells. Apoptosis was measured in primary islets using a cell-permeable dye with a fluorescence readout of activated cleaved caspase-3 and-7.ResultsA de novo motif analysis was performed on a subset of genes previously found to be regulated at the level of ribosome binding during PDX1-deficiency, which identified a poly-cytosine (polyC) motif in the 3'UTR of the transcript encoding JUND. The polyC-binding protein hnRNPK bound to the mRNA encoding JUND, leading us to hypothesize that hnRNPK regulates JUND expression during glucolipotoxicity. Indeed, loss of hnRNPK blocked the post-transcriptional upregulation of JUND during metabolic stress. hnRNPK was phosphorylated in mouse and human islets during glucolipotoxicity and in islets of diabetic db/db mice. The MEK/ERK signaling pathway was both necessary and sufficient for the phosphorylation of hnRNPK, upregulation of JUND levels, and induction of pro-oxidant and pro-inflammatory genes. Further, we identified the RNA helicase DDX3X as a new binding partner for hnRNPK that is required for efficient translation of JUND mRNA. Loss of hnRNPK reduced DDX3X binding to translation machinery, suggesting that these factors cooperate to regulate translation in β cells.ConclusionsOur results identify a novel ERK/hnRNPK/DDX3X pathway that influences β cell survival and is activated under conditions associated with T2D.

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NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells.

Publications

NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells.

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