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Hypermethylation Of ADHFE1 Promotes The Proliferation Of Colorectal Cancer Cell Via Modulating Cell Cycle Progression.

ABSTRACT: Background:Colorectal cancer (CRC) is one of the most common malignancies worldwide. Studies have demonstrated that epigenetic modifications play essential roles in the development of CRC. ADHFE1 is a differentially expressed gene that has been reported to be hypermethylated in CRC. However, the role and mechanism of ADHFE1 in the proliferation of CRC remain unclear. Materials and methods:ADHFE1 expression was analyzed in CRC tissues by IHC and qRT-PCR, and the relationship between ADHFE1 expression and the clinicopathological parameters was analyzed. Cell proliferation were assessed by the in vitro and in vivo experimental models. GSEA assay was performed to explore the mechanism of ADHFE1 in the proliferation of CRC. Flow cytometry and Western blot were used to detect the activation of the cell cycle signaling. Bisulfite genomic sequence (BSP) assay was used to test the methylation degree of ADHFE1 gene promoter in CRC tissues. Results:Here, we verified that ADHFE1 was down-regulated and hypermethylated in CRC tissues. The down-regulation of ADHFE1 was correlated with poor differentiation and advanced TNM stage of CRC patients. And ADHFE1 expression restored when the CRC cell line SW620 was treated with the demethylating agent 5-Aza-CdR. Overexpression of ADHFE1 inhibited the proliferation of CRC, while ADHFE1 knockdown promoted the proliferation of CRC cells in vitro and in vivo. Moreover, ADHFE1 overexpression could induce a significant G1-S cell cycle arrest in CRC cells and vice versa. Conclusion:Hypermethylation of ADHFE1 might promote cell proliferation by modulating cell cycle progression in CRC, potentially providing a new therapeutic target for CRC patients.

SUBMITTER: Hu YH

PROVIDER: S-EPMC6782030 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hypermethylation Of ADHFE1 Promotes The Proliferation Of Colorectal Cancer Cell Via Modulating Cell Cycle Progression.

Hu Yu-Han YH Ma Shuai S Zhang Xiang-Nan XN Zhang Zhe-Ying ZY Zhu Hui-Fang HF Ji Ying-Hua YH Li Jian J Qian Xin-Lai XL Wang Yong-Xia YX

OncoTargets and therapy 20191004

<h4>Background</h4>Colorectal cancer (CRC) is one of the most common malignancies worldwide. Studies have demonstrated that epigenetic modifications play essential roles in the development of CRC. ADHFE1 is a differentially expressed gene that has been reported to be hypermethylated in CRC. However, the role and mechanism of ADHFE1 in the proliferation of CRC remain unclear.<h4>Materials and methods</h4>ADHFE1 expression was analyzed in CRC tissues by IHC and qRT-PCR, and the relationship betwee ...[more]

PMID: 31632063

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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.

Dataset Information

Hypermethylation Of ADHFE1 Promotes The Proliferation Of Colorectal Cancer Cell Via Modulating Cell Cycle Progression.

Publications

Hypermethylation Of ADHFE1 Promotes The Proliferation Of Colorectal Cancer Cell Via Modulating Cell Cycle Progression.

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