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Impact of LDOC1 on gene expression profiling of a human oral keratinocyte cell line CGHNK2

ABSTRACT: Previous studies demonstrated that LDOC1 as a tumor suppressor which epigenetically silenced by cigarette exposure, but the mechanisms through which LDOC1 suppresses tumorigenesis are not well understood. To investigate the moloecular mechanism involved in the LDOC1-mediated tumor suppressing activity, we established a LDOC1-knockdown subline derived from an untransformed human oral keratinocyte cell line CGHNK2, named CGHNK2-shLDOC1, and its corresponding control subline CGHNK2-shCtrl. These two cell lines were subjected to cDNA microarray analysis in order to identified the genes and signaling pathways regulated by LDOC1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149108 | GEO | 2020/12/01

REPOSITORIES: GEO

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Project description:Despite declining incidence and improved survival rate, lung cancer therapeutic outcomes remain unsatisfactory and still is a leading cause of cancer death. Metastasis and treatment resistance hampers the survival of lung cancer patients. Lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Our studies showed that LDOC1 strongly inhibits human LUAD A549 cells invasiveness and LDOC1 knockdown (KD) sensitized A549 cells to cisplatin. The mechanisms have not been fully elucidated.Coimmunoprecipitation-western blot and confocal microscopic analysis demonstrated the interaction between LDOC1 and the E3 ubiquitin ligase RNF40. RNF40 and its paralog RNF20 forms a heterodimer to monoubiquitylate histone H2B on lysine 120. H2B monoubiquitination (H2Bub1) is a prominent epigenetic mark involved in a variety of cellular processes mainly by regulating the transcription of specific gene sets. Our results showed that LDOC1 negatively regulates H2Bub1 in cell lines and specimens of LUAD. The regulatory mechanism may involve the proteasome degradation of H2B and nuclear translocation of RNF40 mediated by LDOC1. Microarray analysis revealed LDOC1 KD caused a global change in gene expression. SLC7A11, which encodes a cystine-glutamate antiporter, is a key component of ferroptosis epigenetically regulated by H2Bub1 and is significantly upregulated in LDOC1-deficient A549 cells, supporting that the increased H2Bub1 level is the cause of transcriptome reprogram triggered by LDOC1 KD. The IPA results and GEPIA database suggested nine genes upregulated by LDOC1 KD were lethal metastasis gene (LM) candidates with their high expression is associated with shorter overall survival of LUAD patients. Genes involved in inhibition of idiopathic pulmonary fibrosis signaling and upregulated in LDOC1 KD cells will be considered as cisplatin-responsive (CS) gene candidates regulated by LDOC1/H2Bub1 axis.We hypothesized that LDOC1 epigenetically affects tumor metastasis and chemotherapy efficacy of LUAD via regulation of H2Bub1. We aimed to meta-analysis the gene expression array data and chromatin immunoprecipitation (ChIP)-sequencing data to identify lethal-metastasis (LM) and cisplatin-responsive (CR) genes that regulated by LDOC1/H2Bub1 axis in LUAD.

Project description:Serum-driven responses, many of which are related to wound healing, are potentially deregulated in cancer development and associated genomic alterations might have prognostic value. The current study assessed fetal bovine serum-induced transcriptomic changes for clinical relevance in head and neck squamous cell carcinoma (HNSCC) using oral keratinocyte models otherwise routinely cultured without serum, including normal keratinocytes (NOK) and the transformed keratinocyte lines SVpgC2a, SqCC/Y1 and LK0412. Bioinformatics-driven analysis of gene expression implicated primarily serum-induced terminal differentiation in NOK including alterations in 99 genes, 13 gene ontology-categories and 6 molecular networks and involvement of 7 key regulator genes. Compared to NOK, the transformed lines expressed around 3-fold lower numbers of differently expressed transcripts, unique sets of gene ontologies, molecular networks and key regulator genes for each line, and consistent absence of terminal differentiation markers. Assessment of the complete in vitro/serum exposure-derived set of differentially expressed genes (totally 180 genes) relative a clinical, information-rich HNSCC data set identified 17 survival-associated genes of which only 12 had previous association to HNSCC. Multi-step validation of the survival-associated genes relative to several independent tumor data sets, including in the Human Gene Expression Map and Human Protein Atlas databases, confirmed novel association to HNSCC for genes COTL1 and INSIG1 and novel poor outcome prediction for the genes CUL4B and PDGFRL. The definition of normal and aberrant serum responses in keratinocyte models therefore coupled new genes to HNSCC including with relevance to prognosis. Analysis of gene expression changes in serum-exposed normal and transformed cells relative the respective un-exposed states. Significantly differentially expressed genes were next assessed by bioinformatics processing using Gene Ontology categories and network analyses. Findings were also validated relative independent HNSCC data sets as well as transcriptomics and proteomics databases.

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Impact of LDOC1 on gene expression profiling of a human oral keratinocyte cell line CGHNK2

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