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CHD1L promotes cell cycle progression and cell motility by up-regulating MDM2 in breast cancer.

ABSTRACT: Chromodomain helicase/ATPase DNA-binding protein 1-like (CHD1L) gene is a novel oncogene amplified in many solid tumors. We investigated its role in breast cancer. CHD1L was over-expressed in 49.1% (57/116) breast cancer patients. Overexpression of CHD1L was significantly associated with younger age at diagnosis (P = 0.016), lymph node involvement (P = 0.040), higher tumor grade (P = 0.027), higher proliferation rate (P = 0.007) and shorter disease-free survival rate (77.2% vs. 91.5%, P = 0.037). A cDNA microarray analysis identified MDM2 as an important downstream target of CHD1L. And MDM2/p53 signaling pathway was showed to be significantly modulated by CHD1L. Further in vitro study showed that overexpression of CHD1L can promote tumorigenesis, metastasis, invasion and cell cycle progress. In vivo study confirmed the tumorigenesis ability of CHD1L. shRNA-mediated CHD1L silencing could abolishes the tumor-promotion effect of CHD1L in vitro and in vivo. In conclusion, CHD1L may promote the progress of breast cancer cells via the MDM2/p53 signaling pathway. This study identified CHD1L as a prognostic factor for breast cancer and MDM2 might be used as a potential target for therapeutic intervention in CHD1L overexpression breast cancer.

SUBMITTER: Wang W

PROVIDER: S-EPMC6456556 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CHD1L promotes cell cycle progression and cell motility by up-regulating MDM2 in breast cancer.

Wang Wei W Wu Jiayi J Fei Xiaochun X Chen Weiguo W Li Yafen Y Shen Kunwei K Zhu Li L

American journal of translational research 20190315 3

Chromodomain helicase/ATPase DNA-binding protein 1-like (CHD1L) gene is a novel oncogene amplified in many solid tumors. We investigated its role in breast cancer. CHD1L was over-expressed in 49.1% (57/116) breast cancer patients. Overexpression of CHD1L was significantly associated with younger age at diagnosis (P = 0.016), lymph node involvement (P = 0.040), higher tumor grade (P = 0.027), higher proliferation rate (P = 0.007) and shorter disease-free survival rate ...[more]

PMID: 30972184

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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.

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CHD1L promotes cell cycle progression and cell motility by up-regulating MDM2 in breast cancer.

Publications

CHD1L promotes cell cycle progression and cell motility by up-regulating MDM2 in breast cancer.

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