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Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS family protein

ABSTRACT: Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS family protein

PROVIDER: PRJNA989608 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25098702.fastq.gz	Fastqsanger.gz
	SRR25098703.fastq.gz	Fastqsanger.gz
	SRR25098704.fastq.gz	Fastqsanger.gz
	SRR25098705.fastq.gz	Fastqsanger.gz
	SRR25098706.fastq.gz	Fastqsanger.gz

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Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS family protein [ATAC]

Project description:Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS family protein [ATAC]

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Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS family protein

Project description:Nectin-4 or PVRL4 is a promising therapeutic target because its augmented expression has been found in a wide range of human cancers. It is of note that Enfortumab Vedotin, an ADC for PVRL4 is clinically used for the treatment of urothelial bladder cancer. In addition, rMV-SLAMblind, a genetically engineered oncolytic measles virus, can infect cancer cells and induce apoptosis through an interaction with PVRL4. Although the transcripts of PVRL4 are elevated in breast, lung and ovarian cancer, the mechanism(s) of its overexpression has not been uncovered. To clarify the regulatory mechanism(s) of its elevated expression in breast cancer cells, we searched for its regulatory region(s) using ATAC-seq and ChIP-seq data. Using breast cancer cells, we identified an enhancer region. Additional analyses disclosed that FOS interacted with the enhancer region, and the alterations of the FOS-binding motifs decreased the reporter activity. Consistent with these data, exogenous expression of FOS enhanced not only the reporter activity but also PVRL4 expression in breast cancer cells. Furthermore, RNA-seq analysis using breast cancer cells treated with PVRL4-siRNA revealed its possible involvement in cytokine response and immune systems. These data suggest that FOS is involved, at least partly, in the regulation of PVRL4 expression in breast cancer cells, and that elevated PVRL4 expression may regulate response of the cancer cells to cytokines and immune systems.

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Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS family protein [ATAC]

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Transcriptionally regulated energy metabolism drives early erythropoiesis

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Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS.

Project description:PVRL4 (or nectin‑4) is a promising therapeutic target since its upregulated expression is found in a wide range of human cancer types. Enfortumab vedotin, an antibody‑drug conjugate targeting PVRL4, is clinically used for the treatment of urothelial bladder cancer. In addition, rMV‑SLAMblind, a genetically engineered oncolytic measles virus, can infect cancer cells and induce apoptosis through interaction with PVRL4. Although PVRL4 transcript levels are elevated in breast, lung and ovarian cancer, the mechanisms of its upregulation have not yet been uncovered. To clarify the regulatory mechanisms of elevated PVRL4 expression in breast cancer cells, Assay for Transposase‑Accessible Chromatin‑sequencing and chromatin immunoprecipitation‑sequencing (ChIP‑seq) data were used to search for its regulatory regions. Using breast cancer cells, an enhancer region was ultimately identified. Additional analyses, including ChIP and reporter assays, demonstrated that FOS interacted with the PVRL4 enhancer region, and that alterations of the FOS‑binding motifs in the enhancer region decreased reporter activity. Consistent with these data, exogenous expression of FOS enhanced the reporter activity and PVRL4 expression in breast cancer cells. Furthermore, RNA‑seq analysis using breast cancer cells treated with PVRL4 small interfering RNA revealed its possible involvement in the cytokine response and immune system. These data suggested that FOS was involved, at least partly, in the regulation of PVRL4 expression in breast cancer cells, and that elevated PVRL4 expression may regulate the response of cancer cells to cytokines and the immune system.

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Project description:Here, by combining transcriptome and proteome profiling, we identified 228 post-transcriptionally regulated genes with strict regulation at the protein level in PSCs. Among them, 84 genes were found necessary for the survival of several cell types including PSCs, and 20 genes were identified as specific for the survival of PSCs. These 20 proteins were upregulated only in PSCs and not in differentiated cells derived from the three germ layers. Subcellular fractionation of the mRNA showed that the expression level of most of the 20 proteins was regulated at the mRNA localization stage from the nucleus to the cytoplasm in PSCs, but their translation efficiency was unchanged compared with other cell types. Together, these results reveal a critical function of post-transcriptionally regulated genes on PSC survival.

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