Epigenetic regulation of IncRNA KCNKI5-ASI in gastric cancer

Long noncoding RNAs (lncRNAs) play an important role in gastric cancer. In this study, we aimed to uncover the epigenetic regulatory mechanism of lncRNA KCNK15-AS1 in gastric cancer progression.

Forty patients were included in the study. The expression of KCNK15-AS1 was detected by real-time PCR (RT-PCR), the promoter of KCNK15-AS1 was detected by methylation-specific PCR, and the luciferase assay was performed to detect the relationship between KCNK15-AS1 and miR-21. The relationship of the proteins was explored by an RNA pull-down assay and RNA immunoprecipitation. Chromatin immunoprecipitation was performed to detect the relationship between the promoter and the protein.

The expression of KCNK15-AS1 was lower in the tumor tissue compared to the normal tissue. KCNK15-AS1 interacted with miR-21. Both the overexpression of KCNK15-AS1 and the knockdown of the expression of miR-21 inhibited proliferation and promoted apoptosis and decreased the level of MMP-9, bcl-2, and MMP-2 but increased the level of Bax. In addition, the methylation of KCNK15-AS1 was detected in the tumor tissue but was not detected in the normal tissue. Treatment with 5-azacytidine and chidamide decreased the level of DNMT1 and HDAC1 and increased the level of KCNK15-AS1. The RNA pull-down and RNA immunoprecipitation results showed that KCNK15-AS1 interacted with DNMT1 and HDAC1. The ChIP-seq result showed that the promoter of MAPK interacted with DNMT1, and the promoter of AKT and STAT5 interacted with HDAC1.

In this study, we identified two regulatory axes, namely KCNK15-AS1-DNMT1-MAPK and KCNK15-AS1-HDAC1-AKT, which were associated with gastric cancer progression. Chidamide and 5-azacytidine might provide new modes for treating gastric cancer.