Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression

Abstract

SET7/9, a histone methyltransferase, has two distinct functions for lysine methylation. SET7/9 methylates non-histone proteins, such as p53, and participates in their posttranslational modifications. Although SET7/9 transcriptionally activate the genes via H3K4 mono-methylation, its target genes are poorly understood. To clarify whether or not SET7/9 is related to carcinogenesis, we studied alterations of SET7/9 in gastric cancers (GCs). Among the 376 primary GCs, 129 cases (34.3%) showed loss or weak expression of SET7/9 protein compared to matched non-cancerous tissues by immunohistochemistry. Reduced SET7/9 expression was significantly correlated with clinical aggressiveness and worse prognosis. Knockdown of SET7/9 in GC cells markedly increased cell proliferation, migration and invasion. Expression of SREK1IP1, PGC and CCDC28B were inhibited in GC cells with SET7/9 knockdown, while matrix metalloproteinase genes (MMP1, MMP7 and MMP9) were activated. SET7/9 bound and mono-methylated H3K4 at the region of the approximately 4-6 kb upstream from the SREK1IP1 transcriptional start site and the promoters of PGC and CDC28B. Cell proliferation, migration and invasion, and expression of three MMPs were increased in GC cells with SREK1IP knockdown, which were similar to those of SET7/9 knockdown. These data suggest that SET7/9 has tumor suppressor functions, and loss of SET7/9 may contribute to gastric cancer progression.

Opposite Effects of SET7/9 on Apoptosis of Human Acute Myeloid Leukemia Cells and Lung Cancer Cells

“…Diverged expression patterns and functions of SET7/9 in different cancer types have been reported. SET7/9 acts as a tumor suppressor in breast cancer and gastric cancer with down-regulated expression in tumor tissues 1 , 15 . However, SET7/9 shows increased expression in prostate cancer and hepatocellular carcinoma and promotes cell proliferation by regulating cell cycle 19 , 30 .…”

“…However, SET7/9 shows increased expression in prostate cancer and hepatocellular carcinoma and promotes cell proliferation by regulating cell cycle 19 , 30 . It is thus suggested that SET7/9 may play distinct roles in tissue- and cancer-specific manners 1 .…”

“…For example, the expression of SET7/9 was associated with gastric cancer progression. Overexpression of SET7/9 inhibited oncogenic activities through regulation of Gli-1 expression in breast cancer 1 , 15 . However, the role of SET7/9 in cancer development is still controversial, which may be partially due to its promiscuous targeting of different substrates 16 .…”

“…Epigenetic regulation of DNA methylation patterns and chromatin structure plays important role in carcinogenesis 1 . Aberrant DNA or histone methylation at CpG islands in promoter regions of tumor suppressor genes can affect tumor progression and has been frequently observed in various cancer types 2 , 3 .…”

Allyl isothiocyanate regulates lysine acetylation and methylation marks in an experimental model of malignant melanoma

“…This histone methyltransferase (HMT) enzyme is known to catalyze the mono-methylation of H3K4 and is also associated with the methylation of non-histone proteins including p53. The role of this HMT in carcinogenesis is controversial as some studies report its tumor suppressor function [67,68] while others associate its activity with increased proliferation [69]. Overall, among all di-and tri-methylated lysines on histone H3 that we examined (K36me2/me3, K4me2/me3, K79me2/me3, K27me2/me3 and K9me2/me3), it was observed that only the expression levels of H3K4me3 were significantly reduced upon exposure to AITC.…”