Dataset Information

EGR1-mediated linc01503 promotes cell cycle progression and tumorigenesis in gastric cancer.

ABSTRACT:

Objectives

Long non-coding RNAs (lncRNAs) are key mediators in various malignancies. Linc01503 was previously elucidated to promote gastric cancer (GC) cell invasion. However, the upstream mechanism of linc01503 and its involvement in GC cell cycle, apoptosis and tumorigenesis still remain unclear.

Materials and methods

Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were implicated to detect linc01503 level in GC. The role of linc01503 was detected by in vitro functional assays and in vivo xenograft tumour models. The association between linc01503 and its upstream effector was identified by chromatin immunoprecipitation (ChIP) assays. The mechanistic model of linc01503 was clarified using subcellular separation, fluorescence in situ hybridization, RNA-sequencing, RNA immunoprecipitation (RIP) and ChIP assays.

Results

Linc01503 was remarkably elevated in GC and tightly linked with the overall survival of patients with GC. The key transcription factor early growth response protein 1 (EGR1) critically activated the transcription of linc01503. Functionally, linc01503 knockdown resulted in the activation of apoptosis and G1/G0 phase arrest in GC. Mechanistically, linc01503 interacted with histone modification enzyme enhancer of zeste 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1), thereby mediating the transcriptional silencing of dual-specificity phosphatase 5 (DUSP5) and cyclin-dependent kinase inhibitor 1A (CDKN1A) in GC.

Conclusions

EGR1-activated linc01503 could epigenetically silence DUSP5/CDKN1A expression to mediate cell cycle progression and tumorigenesis, implicating it as a prospective target for GC therapeutics.

SUBMITTER: Ma Z

PROVIDER: S-EPMC7791171 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

EGR1-mediated linc01503 promotes cell cycle progression and tumorigenesis in gastric cancer.

Ma Zhonghua Z Gao Xiangyu X Shuai You Y Wu Xiaolong X Yan Yan Y Xing Xiaofang X Ji Jiafu J

Cell proliferation 20201103 1

<h4>Objectives</h4>Long non-coding RNAs (lncRNAs) are key mediators in various malignancies. Linc01503 was previously elucidated to promote gastric cancer (GC) cell invasion. However, the upstream mechanism of linc01503 and its involvement in GC cell cycle, apoptosis and tumorigenesis still remain unclear.<h4>Materials and methods</h4>Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were implicated to detect linc01503 level in GC. The role ...[more]

PMID: 33145887

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Project description:BackgroundHistone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy.MethodsTranscriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP-response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys-Asp-Glu-Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer-bearing mouse model was employed to analyze the effect of the HDAC3-KDELR2 axis on tumor growth.ResultsKDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT-PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo.ConclusionOur results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi-the endoplasmic reticulum traffic transport protein to HDAC-controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.

Project description:Background:The stem cell factor SALL4 is reactivated in human cancers. SALL4 plays diverse roles in tumor growth, metastasis, and drug resistance, but its role in tumor metabolism has not been well characterized. Methods:The glycolytic levels of gastric cancer cells were detected by glucose uptake, lactate production, lactate dehydrogenase activity, ATP level, and hexokinase activity. QRT-PCR and western blot were used to detect the changes in the expression of glycolytic genes and proteins. The downstream target genes of SALL4 were identified by microarray. The regulation of hexokinase II (HK-2) by SALL4 was analyzed by luciferase reporter assay and chromatin immunoprecipitation assay. Transwell migration assay, matrigel invasion assay, cell counting assay and colony formation assay were used to study the roles of HK-2 regulation by SALL4 in gastric cancer cells in vitro. The effects of SALL4 on glycolysis and gastric cancer progression in vivo were determined by subcutaneous xenograft and peritoneal metastasis tumor models in nude mice. Results:SALL4 knockdown inhibited glucose uptake, lactate production, lactate dehydrogenase activity, ATP level and hexokinase activity in gastric cancer cells, and decreased the expression of glycolytic genes and proteins. Microarray analysis showed that SALL4 knockdown affected glycolysis-related pathway. The regulation of HK-2 gene expression by SALL4 was confirmed by luciferase reporter assay and chromatin immunoprecipitation assay. HK-2 knockdown abrogated the promotion of glycolysis by SALL4 in gastric cancer cells, indicating that HK-2 acts as a downstream effector of SALL4. Moreover, HK-2 knockdown reversed the promoting role of SALL4 in gastric cancer cell proliferation, migration and invasion, suggesting that SALL4 drives gastric cancer progression by upregulating HK-2. Conclusions:SALL4 promotes gastric cancer progression through HK-2-mediated glycolysis, which reveals a new mechanism for the oncogenic roles of SALL4 in cancer.

Dataset Information

EGR1-mediated linc01503 promotes cell cycle progression and tumorigenesis in gastric cancer.

Objectives

Materials and methods

Results

Conclusions

Publications

EGR1-mediated linc01503 promotes cell cycle progression and tumorigenesis in gastric cancer.

Similar Datasets

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