Loss of histone H3K27me3 up-regulates SLC7A11 in diffuse gastric cancer cells

To map the genome-wide distribution profile of histone H3K27me3 modification in diffuse gastric cancer tissues, identify target genes regulated by H3K27me3, and primarily explore the potential mechanism of its modification reprogramming in the occurrence and development of the tumor.

Normal gastric mucosal tissues and diffuse gastric cancer tissues were harvested from the patients who underwent examinations or treatments in the departments of gastroenterology and gastrointestinal surgery of our medical center between 2021 and 2023. There were 14 patients in the normal group (6 males and 8 females, average age of 46 years) and 14 patients in the gastric cancer group (8 males and 6 females, average age of 63 years). Cleavage under target and tagmentation (CUT&Tag) technology was employed to capture genomic regions modified by H3K27me3, and analyze the reprogramming characteristics of these modifications. RNA sequencing data, data from high-throughput chromosome conformation capture (Hi-C) technology, and publicly available single-cell data were integrated to investigate the target genes regulated by the reprogramming of H3K27me3 modifications in diffuse gastric cancer cells.

The quality of the CUT&Tag and RNA sequencing data met the standards required for subsequent analysis. Histone H3K27me3 modifications in normal gastric mucosa and diffuse gastric cancer tissues were primarily distributed in distal intergenic regions and intronic regions. In gastric cancer tissues, compared to normal tissues, there was significant reprogramming of H3K27me3 modifications, characterized by a marked reduction in overall H3K27me3 signal intensity. The loss of 2912 H3K27me3 signal peaks might lead to the up-regulation of 822 tumor-associated genes. Among them, 56 genes displayed the most significant up-regulation (fold change in signal intensity ≥2, P<0.05), with notable enrichment in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Specifically, the methionine transporter SLC7A5 and the cystine transporter SLC7A11 were found to have the highest expression levels in gastric cancer tissues. Single-cell data revealed that the abnormal overexpression of SLC7A11 in diffuse gastric cancer was primarily observed in tumor epithelial cells. Further validation using public data and immunohistochemical experiments confirmed the elevated expression of SLC7A11 in diffuse gastric cancer, which is associated with poor prognosis in gastric cancer patients.

The reprogramming of histone H3K27me3 modification is an important epigenetic characteristic in diffuse gastric cancer. Loss of H3K27me3 signal peaks may up-regulate the expression of SLC7A11 in diffuse gastric cancer cells, and thereby promote tumor progression.