High expression of GFAT1 predicts unfavorable prognosis in patients with hepatocellular carcinoma

Li, Lili; Shao, Miaomiao; Peng, Peike; Yang, Caiting; Song, Shushu; Duan, Fangfang; Jia, Dongwei; Zhang, Mingming; Zhao, Junjie; Zhao, Ran; Wu, Weicheng; Wang, Lan; Li, Can; Wu, Hao; Zhang, Jie; Wu, Xin; Ruan, Yuanyuan; Gu, Jianxin

doi:10.18632/oncotarget.15164

Cited by 42 publications

(36 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased expression of GFAT was detected in human breast, 16 prostate, 31 colon, 32 pancreatic, 33,34 and bile duct 35 cancer tissues. The GFAT expression was correlated with worse patient survival in breast, 16 pancreatic, 33 and liver 36 in vitro. 16,32,33,36,37 However, opposite to the above trend, GFAT1 was shown to exhibit tumor suppressive activities in gastric cancer, 38 suggesting possible cell-type specific functions of the enzyme in cancer biology.…”

Section: Discussionmentioning

confidence: 95%

“…Increased expression of GFAT was detected in human breast, prostate, colon, pancreatic, and bile duct cancer tissues. The GFAT expression was correlated with worse patient survival in breast, pancreatic, and liver cancer. Furthermore, GFAT was demonstrated to drive malignant cell growth in vitro and in vivo and to promote migration and invasion of various cancer cells in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…The GFAT expression was correlated with worse patient survival in breast, pancreatic, and liver cancer. Furthermore, GFAT was demonstrated to drive malignant cell growth in vitro and in vivo and to promote migration and invasion of various cancer cells in vitro . However, opposite to the above trend, GFAT1 was shown to exhibit tumor suppressive activities in gastric cancer, suggesting possible cell‐type specific functions of the enzyme in cancer biology.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Chen

Kieu

Saxton

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

Platinum anticancer agents are essential components in chemotherapeutic regimens for non–small‐cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum‐based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino‐sugar N‐acetyl‐glucosamine for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by the combination of cisplatin with HBP inhibition. Expression of glutamine:fructose‐6‐phosphate amidotransferase (GFAT), the rate‐limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFATimpaired cell proliferation and exerted synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose‐regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response (UPR). Suppressing GFAT activity resulted in downregulation of BiP that activated inositol‐requiring enzyme 1α, a sensor protein of UPR, and exacerbated cisplatin‐induced cell apoptosis. These data identify GFAT‐mediated HBP as a target for improving platinum‐based chemotherapy for NSCLC.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Chen

Kieu

Saxton

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…There are two different GFAT genes, GFAT1 and GFAT2, and GFAT1 is the major form ubiquitously expressed in human tissues. Previously, aberrant expression of GFAT1 has been demonstrated in several cancers, including hepatocellular carcinoma and pancreatic ductal adenocarcinoma (PDAC) [12,13]. High GFAT1 expression is identified as an independent predictor of adverse clinical outcome for PDAC patients [12].…”

Section: Introductionmentioning

confidence: 99%

GFAT1/HBP/O-GlcNAcylation Axis Regulatesβ-Catenin Activity to Promote Pancreatic Cancer Aggressiveness

Jia

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Reprogrammed glucose and glutamine metabolism are essential for tumor initiation and development. As a branch of glucose and metabolism, the hexosamine biosynthesis pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and contributes to the O-GlcNAcylation process. However, the spectrum of HBP-dependent tumors and the mechanisms by which the HBP promotes tumor aggressiveness remain areas of active investigation. In this study, we analyzed the activity of the HBP and its prognostic value across 33 types of human cancers. Increased HBP activity was observed in pancreatic ductal adenocarcinoma (PDAC), and higher HBP activity predicted a poor prognosis in PDAC patients. Genetic silencing or pharmacological inhibition of the first and rate-limiting enzyme of the HBP, glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), inhibited PDAC cell proliferation, invasive capacity, and triggered cell apoptosis. Notably, these effects can be restored by addition of UDP-GlcNAc. Moreover, similar antitumor effects were noticed by pharmacological inhibition of GFAT1 with 6-diazo-5-oxo-lnorleucine (DON) or Azaserine. PDAC is maintained by oncogenic Wnt/β-catenin transcriptional activity. Our data showed that GFAT1 can regulate β-catenin expression via modulation of the O-GlcNAcylation process. TOP/FOP-Flash and real-time qPCR analysis showed that GFAT1 knockdown inhibited β-catenin activity and the transcription of its downstream target genes CCND1 and MYC. Ectopic expression of a stabilized form of β-catenin restored the suppressive roles of GFAT1 knockdown on PDAC cell proliferation and invasion. Collectively, our findings indicate that higher GFAT1/HBP/O-GlcNAcylation exhibits tumor-promoting roles by maintaining β-catenin activity in PDAC.

show abstract

“…The rate-limiting enzyme of this pathway is glucosaminefructose amidotransferase (GFAT1/2), which is responsible for controlling the flux of metabolites through this pathway. The HBP is highly utilized in a number of cancers, and its inhibition by either targeting GFAT1/2 or by preventing utilization of glutamine (using a glutamine analog 6-diazo-5-oxo-L-norleucine or DON) results in tumor regression (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Targeting tumor-intrinsic metabolic node sensitizes pancreatic cancer to anti-PD1 therapy

Sharma

Gupta

Garrido

et al. 2019

Preprint

View full text Add to dashboard Cite

Conflict of InterestUniversity of Minnesota has a patent for Minnelide, which has been licensed to Minneamrita Therapeutics, LLC. AKS is the co-founder and the Chief Scientific Officer of this company. SB is a consultant with Minneamrita Therapeutics LLC and this relationship is managed by University of Miami.The remaining authors declare no conflict of interest. AbstractPancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA-4, PD-1, PD-L1) has not been very successful against PDAC.The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize UDP-GlcNAc.In the current manuscript, we target this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-L-norleucine or DON). Our results show that DON decreases the self-renewal potential and metastatic ability of tumor cell. Further, treatment with DON results in a decrease in hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM. this in turn, increases CD8+ cytotoxic T-cells infiltration, and makes the tumors tumors more amenable and sensitive to anti-PD1 therapy.

show abstract

High expression of GFAT1 predicts unfavorable prognosis in patients with hepatocellular carcinoma

Cited by 42 publications

References 22 publications

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

GFAT1/HBP/O-GlcNAcylation Axis Regulatesβ-Catenin Activity to Promote Pancreatic Cancer Aggressiveness

Targeting tumor-intrinsic metabolic node sensitizes pancreatic cancer to anti-PD1 therapy

Contact Info

Product

Resources

About