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ZNF350 promoter methylation accelerates colon cancer cell migration.

ABSTRACT: Diversification of transcriptomic and epigenomic states may occur during the expansion of colorectal cancers. Certain cancer cells lose their epithelial characters and gain mesenchymal properties, known as epithelial-mesenchymal transition (EMT), and they aggressively migrate into the non-tumorigenic extracellular matrix. In this study, we isolated a subpopulation with accelerated baseline motility (MG cells) and an immotile one (non-MG cells) from a colon cancer cell line (HCT116). Gene expression signatures of the MG cells indicated that this subpopulation was likely an EMT hybrid. The MG cells substantially lost their migratory properties after treatment with a methyltransferase inhibitor, 5-azacytidine, suggesting a role of DNA methylation in this process. Global transcriptome assays of both types of cells with or without 5-azacytidine treatment identified 640 genes, whose expression might be methylation-dependently down-regulated in the MG cells. Global methylation analysis revealed that 35 out of the 640 genes were hyper-methylated in the MG cells. Among them, we focused on the anti-oncogene ZNF350, which encodes a zinc-finger and BRCA1-interacting protein. Notably, ZNF350 knockdown accelerated migration of the non-MG cells, while overexpression of ZNF350 in the MG cells significantly impaired their migration. Finally, pyrosequence analysis together with dual luciferase assays of serially truncated fragments of the ZNF350 promoter (-268 to +49 bp) indicated that three hyper-methylated sites were possibly responsible for the basal promoter activity of ZNF350. Taken together, our results suggest that hyper-methylation of the ZNF350 proximal promoter may be one of the crucial determinants for acquiring increased migratory capabilities in colon cancer cells.

SUBMITTER: Tanaka H

PROVIDER: S-EPMC6298409 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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<i>ZNF350</i> promoter methylation accelerates colon cancer cell migration.

Tanaka Hiroki H Kuwano Yuki Y Nishikawa Tatsuya T Rokutan Kazuhito K Nishida Kensei K

Oncotarget 20181204 95

Diversification of transcriptomic and epigenomic states may occur during the expansion of colorectal cancers. Certain cancer cells lose their epithelial characters and gain mesenchymal properties, known as epithelial-mesenchymal transition (EMT), and they aggressively migrate into the non-tumorigenic extracellular matrix. In this study, we isolated a subpopulation with accelerated baseline motility (MG cells) and an immotile one (non-MG cells) from a colon cancer cell line (HCT116). Gene express ...[more]

PMID: 30613364

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Project description:BackgroundTo investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer.MethodsWe studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n=13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors.ResultsWe identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity.ConclusionSomatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF.

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ZNF350 promoter methylation accelerates colon cancer cell migration.

Publications

<i>ZNF350</i> promoter methylation accelerates colon cancer cell migration.

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