NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

Bury, Marina; Calvé, Benjamin Le; Lessard, Frédéric; Maso, Thomas Dal; Saliba, James; Michiels, Carine; Ferbeyre, Gerardo; Blank, Volker

doi:10.1016/j.celrep.2019.09.087

Cited by 67 publications

(63 citation statements)

References 68 publications

(67 reference statements)

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“…Several studies have reported that decreased NFE2L3 expression inhibits proliferation of cells 15 , 18 . To investigate the potential effect of NFE2L3 on HepG2 cell proliferation, NFE2L3 shRNA interference lentiviral vector was performed to knockdown NFE2L3.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with the above results, the expression of CDK2 and PCNA also decreased, it is further confirmed that NFE2L3 plays an important role in cell growth and proliferation. Cyclin D1 is a key mediator of cell growth and proliferation, some researches had proved that NFE2L3 regulated the expression of cyclin D1 in CRC while another article pointed out that the silencing of NFE2L3 will increase the level of DUX4, a direct inhibitor of CDK1, and reduce the proliferation and tumorigenicity of colon cancer cells 15 , 18 . In addition, both cytoplasmic and nuclear β-catenin were decreased by knockdown NFE2L3, indicating NFE2L3 significantly regulated transcription of β-catenin in liver cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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NFE2L3 promotes malignant behavior and EMT of human hepatocellular carcinoma (HepG2) cells via Wnt/β‑catenin pathway

Ren¹,

Wang²,

Hao³

et al. 2020

J. Cancer

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Objective: NFE2L3 is a member of the cap 'n' collar basic-region leucine zipper family. NFE2L3 has turned out to be associated with oxidative stress, but the relevance of NFE2L3 in hepatocellular carcinoma (HCC) has remained elusive. This study aimed to investigate the role of NFE2L3 in HCC and explore underlying mechanisms. Methods: Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the mRNA and protein expression of NFE2L3, the expression of epithelial-mesenchymal transition (EMT) markers and Wnt/β-catenin signaling pathway-related proteins. In loss-function experiments, HepG2 cells were transfected with lentiviral vector containing NFE2L3 short hairpin RNA or scramble control. Cell proliferation and migration were measured by Cell Counting Kit-8, Colony formation, EdU incorporation and Transwell assays respectively. Flow cytometry was used to analyze cell cycle and apoptosis. HepG2 cells were subcutaneously injected into nude mice and tumor size was measured once every other day. Results: The results revealed that high expression of NFE2L3 was positively associated with malignant behavior and EMT in HCC. Knockdown of NFE2L3 inhibited cell proliferation and migration, led to cell cycle G0/G1 arrest and induction of cell apoptosis, increased expression of E-cadherin and decreased expression of N‑cadherin, Vimentin, MMP2, CDK2 and PCNA. In addition, tumor growth was inhibited by silencing of NFE2L3 in vivo . Expression of β-catenin and Wnt target genes cyclin D1 and TCF4 was reduced in HepG2-shNFE2L3 cells. Conclusions: NFE2L3 promotes cell proliferation, metastasis, and induces EMT of hepatocellular carcinoma (HepG2) cells via activation of Wnt/β-catenin pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NFE2L3 promotes malignant behavior and EMT of human hepatocellular carcinoma (HepG2) cells via Wnt/β‑catenin pathway

Ren¹,

Wang²,

Hao³

et al. 2020

J. Cancer

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“…We guess another biological meaning of our findings in cancer. The functional difference between NRF3 and NRF1 is not in the regulation of the proteasome activity rather in the expression of cancer-related genes such as VEGFA and DUX4 that other groups have recently identified as NRF3-specific target genes 19,20 . Meanwhile, cancer cells have to keep NRF1 as a backup for proteasome regulation, because the proteasome activity is crucial for more rapid proliferation of cancer cells 21 .…”

Section: Discussionmentioning

confidence: 99%

NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression

Waku

Katayama

Hiraoka

et al. 2020

Preprint

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29Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial 30 for cancer cell growth. However, the mechanism of how proteasome activity is maintained in 31 cancer cells has remained unclear. The CNC family transcription factor NRF1 induces the 32 expression of almost all proteasome-related genes under proteasome inhibition. NRF1 and its 33 phylogenetically closest homolog NRF3 are both highly expressed in several types of cancers, 34 such as colorectal cancer. Herein, we demonstrate that NRF1 and NRF3 complementarily 35 maintain basal proteasome activity in cancer cells. A double knockdown of NRF1 and NRF3 36 impaired the basal proteasome activity in cancer cells and the cancer cell resistance to a 37 proteasome inhibitor anticancer drug bortezomib by significantly reducing basal expression of 38 seven proteasome-related genes, including PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, 39 and POMP. Interestingly, the molecular basis behind these cellular consequences was that NRF3 40 repressed NRF1 translation by the gene induction of translational regulator CPEB3, which binds 41 to NRF1-3′UTR and decreases polysome formation on NRF1 mRNA. Consistent results were 42 obtained from clinical analysis, wherein patients with cancer having higher CPEB3/NRF3-43 expressing tumors exhibit poor prognosis. These results provide the novel regulatory mechanism 44 of basal proteasome activity in cancer cells through an NRF3-CPEB3-NRF1 translational 45 repression axis. 46 65 including PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, and POMP. Interestingly, NRF366 represses NRF1 translation by inhibiting polysome formation on NRF1 mRNA. We identify a 67 translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein 3) as an 68NRF3-target gene that is involved in the repression of NRF1 translation. A functional CPEB 69 recognition motif is also identified in the NRF1-3′UTR. Furthermore, we validate that CPEB3 is 70 a key factor for not only the complementary maintenance of a basal proteasome activity by NRF1 71 and NRF3 but also the poor prognosis of colorectal cancer patients with tumors highly expressing 72 NRF3, but not NRF1. In conclusion, we demonstrate the novel regulatory mechanism of basal 73 proteasome activity in cancer cells where NRF1 and NRF3 complementarily, but not 74 4 simultaneously, maintain the basal expression of proteasome-related genes through CPEB3-75 mediated translational repression. 77 Results 78Both NRF1 and NRF3 are required to maintain a basal proteasome activity in cancer cells 79Initially, we investigated the biological relevance of NRF1 and NRF3 for proteasome activity at 80 the basal level in living cancer cells. Using human colorectal carcinoma HCT116 cells, we 81 generated cells which stably expressed the ZsProSensor-1 fusion protein, a proteasome-sensitive 82 fluorescent reporter ( Supplementary Fig. 1A). Once the proteasome in this stable cell line was 83 inhibited by proteasome inhibitor MG-132, green fluorescence derived from the reporter pr...

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“…Xue et al [37] reported that the activity of CDK1 is highly elevated in CRC tissues compared to noncancerous tissues, and it predicts distant metastasis risk in CRC; CDK1 can promote the progression of CRC through phosphorylation of JAK1 to activate the JAK/ STAT3 signaling pathway. Bury et al [38] indicated that high gene expression levels of CDK1 stimulated the proliferation and migration of colorectal cancer cells, and inhibition of CDK1 activity by using inhibitors can inhibit the proliferation of colorectal cancer cells in vitro and in vivo. In addition, Zhang et al [39] indicated that frequent overexpression of CDK1 in human CRCs is associated with the therapeutic target, and the therapeutic resistance of BRAF mutant human CRC can be suppressed by targeting CDK1.…”

Section: Mki67mentioning

confidence: 99%

CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis

Wang

et al. 2020

World J Surg Onc

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Background: Colorectal cancer (CRC) is one of the most common malignancies of the digestive system, which causes severe financial burden worldwide. However, the specific mechanisms involved in CRC are still unclear. Methods: To identify the significant genes and pathways involved in the initiation and progression of CRC, the microarray dataset GSE126092 was downloaded from Gene Expression Omnibus (GEO) database, and then, the data was analyzed to identify differentially expressed genes (DEGs). Subsequently, the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on these DEGs using the DAVID database, and the protein-protein interaction (PPI) network was constructed using the STRING database and analyzed using the Cytoscape software. Finally, hub genes were screened, and the survival analysis was performed on these hub genes using the Kaplan-Meier curves in the cBioPortal database. Results: In total, 937 DEGs were obtained, including 316 upregulated genes and 621 downregulated genes. GO analysis revealed that the DEGs were mostly enriched in terms of nuclear division, organelle fission, cell division, and cell cycle process. KEGG pathway analysis showed that the DEGs were mostly enriched in cell cycle, oocyte meiosis, cytokine-cytokine receptor interaction, and cGMP-PKG signaling pathway. The PPI network comprised 608 nodes and 3100 edges, and 4 significant modules and 10 hub genes with the highest degree were identified using the Cytoscape software. Finally, survival analysis showed that overexpression of CDK1 and CDC20 in patients with CRC were statistically associated with worse overall survival. Conclusions: This bioinformatics analysis revealed that CDK1 and CDC20 might be candidate targets for diagnosis and treatment of CRC, which provided valuable clues for CRC.

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NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

Cited by 67 publications

References 68 publications

NFE2L3 promotes malignant behavior and EMT of human hepatocellular carcinoma (HepG2) cells via Wnt/β‑catenin pathway

NFE2L3 promotes malignant behavior and EMT of human hepatocellular carcinoma (HepG2) cells via Wnt/β‑catenin pathway

NRF1 and NRF3 complementarily maintain a basal proteasome activity in cancer cells through CPEB3-mediated translational repression

CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis

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