High glucose upregulates FOXM1 expression via EGFR/STAT3 dependent activation to promote progression of cholangiocarcinoma

Detarya, Marutpong; Thaenkaew, Salak; Seubwai, Wunchana; Indramanee, Somsiri; Phoomak, Chatchai; Saengboonmee, Charupong; Wongkham, Sopit; Wongkham, Chaisiri

doi:10.1016/j.lfs.2021.119114

Cited by 13 publications

(7 citation statements)

References 44 publications

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“…36 STAT3 induces the downstream upregulation of the transcription factor FOXM1 (forkhead box protein M1), which is responsible for the aggressive phenotype of CCA cells cultured in high glucose. 37 Other pathways participate in the promotion of CCA growth in conditions of hyperglycaemia, including ROSmediated upregulation of chromodomain helicase DNA-binding protein 8 and mannosidase alpha class 2a member 2, 38 increased expression of DPY30 (a subunit of the SET1 and MLL family methyltransferase complexes), 39 the long noncoding RNA FAM66 40 and SIRT3-dependent activation of the HIF1a/PDK1/pyruvate dehydrogenase axis 41 (Fig. 1).…”

Section: Cca and Glucose Metabolismmentioning

confidence: 99%

Metabolic reprogramming in cholangiocarcinoma

Raggi

Taddei

Rae

et al. 2022

Journal of Hepatology

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Section: Cca and Glucose Metabolismmentioning

confidence: 99%

Metabolic reprogramming in cholangiocarcinoma

Raggi

Taddei

Rae

et al. 2022

Journal of Hepatology

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“…Compared with small molecule PROTACs, the design and synthesis of p-PROTACs is simpler, and possess the ability to target “undruggable” targets with high specificity and low toxicity, and can resist to mutation targets. Since GLUT1 levels can correlate with response to FOXM1, there is increasing interest in understanding cell proliferation and glycolysis [ 42 , 43 ]. However, while PD-L1 regulation has been extensively studied in cancer cells, the specific link between PD-L1 and FOXM1 has received less attention.…”

Section: Discussionmentioning

confidence: 99%

Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression

Wang

Dai

Yu³

et al. 2022

J Exp Clin Cancer Res

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Background Peptide proteolysis-targeting chimeras (p-PROTACs) with advantages of high specificity and low toxicity have emerged as a powerful technology of targeted protein degradation for biomedical applications. FOXM1, a proliferation-associated transcription factor, is overexpressed in a variety of human tumors as a key driver of tumorigenesis and cancer progression, and is a potential anticancer therapeutic target. However, FOXM1-targeting p-PROTACs has not been researched. Methods Here, we first analyzed the expression of FOXM1, GLUT1 and PD-L1 in liver cancer through database and clinical samples of patients. FOXM1-targeting peptides, selected by screening phage display library, are verified its targeting effect by immunofluorescence and CCK-8 test. The novel p-PROTAC degrader of FOXM1 is chemically synthesis, named FOXM1-PROTAC, by linking a FOXM1-binding antagonistic peptide, with the E3 ubiquitin ligase recruitment ligand Pomalidomide and with the cell membrane penetrating peptide TAT. Its degradation effect on FOXM1 was detected by Western blotting, qPCR, and we verified its effect on the behavior of cancer cells by flow cytometry, scratch assay, and Transwell in vitro. The tumor xenografted mice model was used for evaluating FOXM1-PROTAC therapeutic response in vivo. Finally, we detected the expression of GLUT1 and PD-L1 after FOXM1-PROTAC degraded FOXM1 by using Western Blotting and hippocampal detectors and dual immunofluorescence. Results We found that the novel FOXM1-PROTAC efficiently entered cells and induced degradation of FOXM1 protein, which strongly inhibits viability as well as migration and invasion in various cancer cell lines, and suppressed tumor growth in HepG2 and MDA-MB-231 cells xenograft mouse models, without detected toxicity in normal tissues. Meanwhile, FOXM1-PROTAC decreased the cancer cells glucose metabolism via downregulating the protein expression levels of glucose transporter GLUT1 and the immune checkpoint PD-L1, which suggests involvement of FOXM1 in cancer cell metabolism and immune regulation. Conclusions Our results indicate that biologically targeted degradation of FOXM1 is an attractive therapeutic strategy, and antagonist peptide-containing FOXM1-PROTACs as both degrader and inhibitor of FOXM1 could be developed as a safe and promising drug for FOXM1-overexpressed cancer therapy.

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“…The tight interconnection between O-GlcNAcylation and glucose metabolism prompted us to explore the mechanistic insight as to how K18 O-GlcNAcylation affects its interaction. [50][51][52] We transfected HuCCT1 shK18 stable cell line with FLAG-K18 WT or FLAG-K18 S30A with equivalent protein expression level, co-immunoprecipitated the K18-interacting proteins with anti-FLAG beads and subjected to LC-MS/MS analysis (Figures S20A and S20B). We identified 858 up-regulated (fold change > 1.50, P < 0.05) interacting proteins in FLAG-K18 WT HuCCT1 cells compared to FLAG-K18 S30A cells (Figure 6A), the majority of which were closely related to the TCA cycle shown (which was not certified by peer review) is the author/funder.…”

Section: K18 O-glcnacylation Promotes K18-isocitrate Dehydrogenase In...mentioning

confidence: 99%

O-GlcNAcylation of Keratin 18 coordinates TCA cycle to promote cholangiocarcinoma progression

Meng

Zhou

Liu

et al. 2023

Preprint

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Glycosylation in human cholangiocarcinoma (CCA) actively contributes to pathophysiological steps of tumor progression. Of note is the dynamic modification of proteins by O-linked beta-N-acetyl-glucosamine (O-GlcNAcylation) that modulates various tumor-associated biological activities. By using a cutting-edge chemical proteomic methodology for intact glycopeptide analysis, we show herein that O-GlcNAcylation of Keratin 18 (K18) coordinates the tricarboxylic acid (TCA) cycle enzymes, namely isocitrate dehydrogenases (IDHs), to promote CCA progression. Mechanistically, site-specific O-GlcNAcylation of K18 on Ser 30 stabilizes K18, which benefits the expression of cell cycle checkpoints to enhance cell cycle progression and cell growth. Interaction with IDHs down-regulates the level of citrate and isocitrate, while up-regulates the level of α-ketoglutarate (alpha-KG). Our study thus expands the current understanding of protein O-GlcNAcylation, and adds another dimension of complexity to post-translational control over metabolism and tumorigenesis.

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High glucose upregulates FOXM1 expression via EGFR/STAT3 dependent activation to promote progression of cholangiocarcinoma

Cited by 13 publications

References 44 publications

Metabolic reprogramming in cholangiocarcinoma

Metabolic reprogramming in cholangiocarcinoma

Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression

O-GlcNAcylation of Keratin 18 coordinates TCA cycle to promote cholangiocarcinoma progression

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