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Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

ABSTRACT:

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The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in metastasis, but neither the mechanisms involved in this process nor the role of the different isoforms of the gene are known. Here we show that the ratio of these isoforms is related to the relapsing of the disease, and that the protein ZNF518B interacts with enzymes able to introduce epigenetic changes, which may affect the activity of many genes. We also report a list of genes affected in common by ZNF518B and by two of those related enzymes, namely, G9A and EZH2. An in-depth analysis of five of those genes revealed that ZNF518B is involved in the recruitment of the enzymes and in the deposition of the corresponding epigenetic marks. The results highlight the relevance of epigenetic changes in cancer development, and open the possibility of developing therapeutic approaches, as the introduction of epigenetic modifications is reversible.

Abstract

The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.

SUBMITTER: Gimeno-Valiente F

PROVIDER: S-EPMC8004037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

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