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Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape.

ABSTRACT: The Tim-3-galectin-9 secretory pathway is known to protect various types of cancer cells against host immune surveillance. We found that pharmacologically induced mitochondrial dysfunction leads to a reduced galectin-9 expression/exocytosis in human colorectal cancer cells and re-distribution of this protein (the effect described for various cellular proteins) into mitochondria.

SUBMITTER: Sakhnevych SS

PROVIDER: S-EPMC6461007 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape.

Sakhnevych Svetlana S SS Yasinska Inna M IM Fasler-Kan Elizaveta E Sumbayev Vadim V VV

Frontiers in pharmacology 20190405

The Tim-3-galectin-9 secretory pathway is known to protect various types of cancer cells against host immune surveillance. We found that pharmacologically induced mitochondrial dysfunction leads to a reduced galectin-9 expression/exocytosis in human colorectal cancer cells and re-distribution of this protein (the effect described for various cellular proteins) into mitochondria. ...[more]

PMID: 31024310

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Project description:BackgroundColorectal cancer (CRC) is the third most commonly diagnosed human malignancy worldwide. Upregulation of inhibitory immune checkpoints by tumor-infiltrating immune cells (TIICs) or their ligands by tumor cells leads to tumor evasion from host immunosurveillance. Changes in DNA methylation pattern and enrichment of methylated histone marks in the promoter regions could be major contributors to the upregulation of immune checkpoints (ICs) in the tumor microenvironment (TME).MethodsRelative expressions of various immune checkpoints and ligands in colon normal tissues (NT) and colorectal tumor tissues (TT) were assessed by qRT-PCR. The epigenetic modifications behind this upregulation were determined by investigating the CpG methylation status of their promoter regions using bisulfite sequencing. Distributions of histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) in promoter regions of these genes were assessed by chromatin immunoprecipitation (ChIP) assay.ResultsWe found that the expression levels of PD-1, CTLA-4, TIM-3, TIGIT, PD-L1, and galectin-9 were significantly higher in colorectal tumor tissues, compared with colon normal tissues. To study the role of DNA methylation, we checked the promoter CpG methylation of ICs and ligands and found that only CTLA-4 and TIGIT, among other genes, were significantly hypomethylated in TT compared with NT. Next, we checked the abundance of repressive histones (H3K9me3 and H3K27me3) in the promoter regions of ICs/ligands. We found that bindings of H3K9me3 in PD-1 and TIGIT promoters and H3K27me3 in CTLA-4 promotor were significantly lower in TT compared with NT. Additionally, bindings of both H3K9me3 and H3K27me3 in the TIM-3 promoter were significantly lower in TT compared with NT.ConclusionThis study shows that both DNA hypomethylation and H3K9me3 and H3K27me3 repressive histones are involved in upregulation of CTLA-4 and TIGIT genes. However, repressive histones, but not DNA hypomethylation, are involved in upregulation of PD-1 and TIM-3 genes in CRC tumor tissue. These epigenetic modifications could be utilized as diagnostic biomarkers for CRC.

Dataset Information

Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape.

Publications

Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape.

Similar Datasets

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