scholarly journals O-GlcNAc modification of oncogenic transcription factor Sox2 promotes protein stability and regulates self-renewal in pancreatic cancer

2018 ◽  
Author(s):  
Nikita S Sharma ◽  
Vineet K Gupta ◽  
Patricia Dauer ◽  
Kousik Kesh ◽  
Roey Hadad ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
The United States ◽  
Tumor Initiation ◽  
Self Renewal ◽  
Pancreatic Cancer Cells ◽  
Glcnac Transferase ◽  
First Time

AbstractPancreatic cancer is among the 3rdleading cause of cancer related deaths in the United States along with a 5-year survival rate of 7%. The aggressive biology of the disease is responsible for such dismal outcome and is manifested by an increase in self-renewal capacity of the cancer cells, which leads to an increased rate of tumor-recurrence, contributing to poor prognosis. Transcription factor SOX2 maintains a critical balance between differentiation and “stemness” and is thus tightly regulated within a cell. In cancer, SOX2 is aberrantly “turned-on” leading to activation of self-renewal pathways in cancer. Regulation of Sox2 in cancer is poorly understood. In the current study, we show for the first time that in pancreatic cancer, Sox2 is modified by addition of O-GlcNAc moiety, catalyzed by OGT (O-GlcNAc Transferase) at S246. This activates Sox2 transcriptional activity by stabilizing the protein in the nucleus. A CRISPR-OGT knockout in pancreatic cancer cell line S2VP10 resulted in a delayed tumor initiation. We further showed that mutation of this site (S246A) prevents the modification of Sox2 and its downstream activity. Our study also demonstrated that targeting OGTin vivowith a small molecule inhibitor OSMI, results in decreased tumor burden, delayed tumor progression and a decreased expression of SOX2 in pancreatic cancer cells. Our study highlights for the first time that that the O-GlcNAc transferase dependent SOX2 glycosylation has a profound effect on the transcriptional activity of SOX2 and is instrumental in determining self-renewal in pancreatic cancer.SignificanceOur study highlights for the first time that that the O-GlcNAc transferase dependent SOX2 glycosylation determines self-renewal in pancreatic cancer which is responsible for tumor initiation.

scholarly journals Hypoxia-driven oncometabolite L-2HG maintains “stemness”-differentiation balance and facilitates immune suppression in pancreatic cancer

2020 ◽  
Author(s):  
Vineet K Gupta ◽  
Nikita S Sharma ◽  
Brittany Durden ◽  
Vanessa T Garrido ◽  
Kousik Kesh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell Activation ◽  
Immune Suppression ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Isomeric Form ◽  
Spectrometric Analysis ◽  
Self Renewal ◽  
Pancreatic Cancer Cells ◽  
First Time

Abstract2-hydroxyglutarate (2-HG) has gained considerable importance in glioma and blood cancers that have mutations in the IDH1/2 gene. In the current study we show for the first time that pancreatic tumors produce 2HG in the absence of IDH1/2 mutation. Our study shows that hypoxic pancreatic tumors that have activated lactate dehydrogenase (LDH) activity, produce the L-isoform of 2HG.Metabolic mass spectrometric analysis along with chiral derivatization showed that pancreatic cancer cells as well as stromal cells secrete the L-isomeric form of 2-hydroxyglutarate (L-2HG) when exposed to hypoxic environment. Serum analysis of human pancreatic cancer patients also showed similar accumulation of L-2HG. Our results showed that this abnormally accumulated L-2HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (Pdx-1, HB9, NKX6.1). Further analysis showed that secreted L-2HG mediates cross talk with immune T-cells and hampers their proliferation and migration thereby suppressing the anti-tumor immunity. In vivo targeting of LDH enzyme with inhibitor (GSK2837808A) showed decrease in L-2HG as well as subsequent tumor regression and sensitization to immune-checkpoint therapy.Present study shows for the first time that hypoxia mediated accumulation of L-2HG drives self-renewal in pancreatic cancer by shifting critical balance of gene expression towards stemness and promotes immune suppression by impairing T cell activation in this disease. Additionally, it indicates that targeting LDH can sensitize pancreatic tumors to anti-PD1 therapy by decreasing L-2HG and reverting their immune evasive function.

scholarly journals DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1101 ◽  
Author(s):  
Asfar S. Azmi ◽  
Yiwei Li ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Nuclear Export ◽  
The United States ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Multiple Tumor ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

Discovery of a novel human lactate dehydrogenase A (LDHA) inhibitor as an anti-proliferation agent against MIA PaCa-2 pancreatic cancer cells

RSC Advances ◽  
2016 ◽  
Vol 6 (28) ◽  
pp. 23218-23222 ◽  
Author(s):  
Yunpeng Sun ◽  
Chonglin Tao ◽  
Fuxiang Yu ◽  
Wenjun Yang ◽  
Yunfeng Shan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Lactate Dehydrogenase ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Proliferation Activity ◽  
First Time

A potent LDHA inhibitor with anti-proliferation activity against MIA PaCa-2 cancer cells was first time reported.

scholarly journals The transcription factor HOXB7 regulates ERK kinase activity and thereby stimulates the motility and invasiveness of pancreatic cancer cells

2017 ◽  
Vol 292 (43) ◽  
pp. 17681-17702 ◽  
Author(s):  
Makiko Tsuboi ◽  
Keisuke Taniuchi ◽  
Takahiro Shimizu ◽  
Motoaki Saito ◽  
Toshiji Saibara
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Kinase Activity ◽  
Pancreatic Cancer Cells ◽  
Erk Kinase
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