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Oncogenic zinc finger protein ZNF322A promotes lung cancer stemness through transcriptionally suppressing c-Myc expression [ChIP-Seq]

ABSTRACT: ZNF322A, a C2H2 zinc finger transcription factor, is an oncoprotein in lung cancer. However, the transcription mechanisms of ZNF322A in lung cancer stemness remain elusive. By integrating our chromatin immunoprecipitation-sequencing and RNA-sequencing datasets, we identified and validated transcriptional targets of ZNF322A, which significantly enriched in developmental processes. Indeed, overexpression of ZNF322A promoted self-renewal ability and increased stemness-related gene expressions in vitro and in vivo. Importantly, ZNF322A bound directly to c-Myc promoter to transcriptionally suppress c-Myc expression, which in turn increased mitochondrial oxidative phosphorylation, promoted cell motility and thus maintained lung cancer stemness properties. Clinically, ZNF322AHigh/c-MycLow expression profile was revealed as an independent factor for poor outcome of lung cancer patients. Our study provides first evidence that ZNF322A-centered transcriptome promotes lung tumorigenesis and ZNF322A acts as a transcription suppressor of c-Myc to maintain lung cancer stemness by shifting metabolism phenotype to oxidative phosphorylation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94656 | GEO | 2019/09/25

REPOSITORIES: GEO

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Oncogenic zinc finger protein ZNF322A promotes lung cancer stemness through transcriptionally suppressing c-Myc expression [RNA-Seq]

Project description:ZNF322A, a C2H2 zinc finger transcription factor, is an oncoprotein in lung cancer. However, the transcription mechanisms of ZNF322A in lung cancer stemness remain elusive. By integrating our chromatin immunoprecipitation-sequencing and RNA-sequencing datasets, we identified and validated transcriptional targets of ZNF322A, which significantly enriched in developmental processes. Indeed, overexpression of ZNF322A promoted self-renewal ability and increased stemness-related gene expressions in vitro and in vivo. Importantly, ZNF322A bound directly to c-Myc promoter to transcriptionally suppress c-Myc expression, which in turn increased mitochondrial oxidative phosphorylation, promoted cell motility and thus maintained lung cancer stemness properties. Clinically, ZNF322AHigh/c-MycLow expression profile was revealed as an independent factor for poor outcome of lung cancer patients. Our study provides first evidence that ZNF322A-centered transcriptome promotes lung tumorigenesis and ZNF322A acts as a transcription suppressor of c-Myc to maintain lung cancer stemness by shifting metabolism phenotype to oxidative phosphorylation.

2019-09-25 | GSE94537 | GEO

Gene expression profiles of human breast cancer cell lines

Project description:Numerous epithelial-to-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis or metastasis, as well as chemoresistance of cancer. However, the underlying mechanism mediating these processes is unclear. Here we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. We identify Twist1, Zeb2, and PDGFRM-NM-1 and M-NM-2 as Foxq1 downstream targets using an expression profiling assay. Further studies reveal that PDGFRM-NM-1 and M-NM-2 can be directly regulated by Foxq1, or indirectly through Twist1. Knockdown of both PDGFRM-NM-1 and M-NM-2 shows more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown by either PDGFRM-NM-1 or M-NM-2 alone. PDGFRM-NM-2, but not PDGFRM-NM-1, shows potent effects in reversing Foxq1-promoted stemness traits. Moreover, pharmacological inhibition or gene silencing of PDGFRs sensitize mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively indicate PDGFRs as critical mediators underlying breast cancer tumorigenesis and chemoresistance driven by EMT promoting genes, which have potential clinical implications for cancer therapy. The purpose of these experiments is to investigate the downstream targets of several transcriptional factors including Foxq1 and IRX5. Another purpose is to compare the expression pattern between basal-like breast cancer cells including MDA-MB231, SUM159 and SUM1315.

2013-05-11 | E-GEOD-46834 | biostudies-arrayexpress

Comparison of gene expression profiles human mesenchymal stromal cells (MSC) cultured in 5% oxygen atmosphere and 19.95% oxygen

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2021-03-03 | GSE168055 | GEO

Plakophilin 1 enhances MYC expression to promote squamous cell lung cancer

Project description:Plakophilin 1 (PKP1) is a component of desmosomes. Although desmosome function loss has been associated with increased cell migration and pro-oncogenic activity, we previously observed PKP1 overexpression in squamous cell lung cancer (SqCLC). We developed in vitro and in vivo functional models of PKP1 gain/loss in SqCLC to explore this paradox. Greater cell dissemination but reduced cell proliferation was observed in CRISPR-Cas9 PKP1-knockout clones. PKP1 expression promoted cell proliferation, cell survival, and in vivo xenograft engraftment, and these pro-oncogenic activities were mediated by the functional relationship of PKP1 with MYC. PKP1 bound to the 5’UTR of MYC mRNA, enhancing MYC translation, and MYC bound directly to the PKP1 promoter, enhancing PKP1 transcription. We propose PKP1 as a novel oncogene in SqCLC and a post-transcriptional regulator of MYC. PKP1 may be a valuable diagnostic biomarker and potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may indirectly target MYC, a primary anti-cancer target.

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S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [HeLa RNA-seq]

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S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [MCF-7 RNA-seq]

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Oncogenic zinc finger protein ZNF322A promotes lung cancer stemness through transcriptionally suppressing c-Myc expression

Project description:Oncogenic zinc finger protein ZNF322A promotes lung cancer stemness through transcriptionally suppressing c-Myc expression

| PRJNA371741 | ENA

Quantitative phosphoproteomics analysis uncovers the regulatory networks of ZNF322A in lung cancer cells

Project description:Cys2His2 (C2H2)-type zinc finger (ZNF) is one of the most common DNA-binding motif and plays a major role as transcription factors, which encoded by 2% of human genes. C2H2 type ZNFs are reported as proteins of great versatility, such as regulation of differentiation, development, metabolism, cell survival, apoptosis, and autophagy. To uncover ZNF322A-mediated functional network, we applied phosphopeptide enrichment and isobaric labeling strategies with MS-based proteomics, and identified 2754 phosphorylation sites on 976 phosphoproteins.

2021-09-08 | PXD015936 | Pride

ME-344 and Bevacizumab in Previously Treated Metastatic Colorectal Cancer

Project description:This is a Phase 1b open-label, multiple dose/schedule sequential study to determine the safety and efficacy of the oxidative phosphorylation (OxPhos) pathway inhibitor ME-344 in combination with bevacizumab in subjects with recurrent mCRC.

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RASSF1A controls Tissue Stiffness and Cancer Stem-like Cells in Lung Adenocarcinoma

Project description:Lung cancer remains the leading cause of cancer-related death due to poor treatment responses and resistance arising from tumor heterogeneity. Here we show that adverse prognosis associated with epigenetic silencing of the tumour suppressor RASSF1A is due to increased deposition of extracellular matrix (ECM), tumour stiffness and metastatic dissemination in vitro and in vivo. We find that lung cancer cells with RASSF1A promoter methylation display constitutive nuclear YAP1 and expression of collagen prolylhydroxylase (P4HA2) which increases collagen deposition. Furthermore, we identify that elevated collagen creates a stiff-ECM which in turn triggers cancer stem-like programming and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverse these effects and increase markers of lung differentiation (TTF-1, Mucin5B). Our study identifies RASSF1A as a clinical biomarker associated with mechanical properties of ECM which increases levels of cancer stemness and risk of metastatic progression in lung adenocarcinoma. Moreover, we highlight P4HA2 as a potential target for uncoupling ECM signals that support cancer stemness.

2019-05-20 | PXD012694 | Pride

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