RIZ1 and histone methylation status in pituitary adenomas

Abstract

RIZ1 displays strong tumor-suppressive activities, which has a potential histone methyltransferase activity. The objective of the study was to evaluate the level and the methylation status of RIZ1 and analyze its association with clinicopathological features and the histone in the pituitary adenomas. We found that RIZ1-positive cases were 11/50 and H-Scores 22.75 ± 11.83 in invasive pituitary adenomas and 26/53 and 66.3 ± 21.7 in non-invasive pituitary adenomas (χ = 8.182, p = 0.004). RIZ1 and C-myc showed the opposite trend in these cases. The methylation levels of RIZ1 were more than 50% in 30.4% (7/23) CpG sites through MALDI-TOF Mass array. There was significant difference (p < 0.01) in 4 CpG sites between invasive pituitary adenoma group and non-invasive pituitary adenoma group; furthermore, the relieved methylation levels of H3K4/H3K9 and enhanced methylation levels of H3K27 in the patients' serum were found. Furthermore, there was statistic difference of H3K4 and H3K27 methylation between invasive pituitary adenoma and non-invasive pituitary adenoma group (p < 0.01). The average progression-free survival in high RIZ1 group was 52.63 ± 7.62 months and 26.06 ± 4.23 months in low RIZ1 group (p < 0.05). Promoter region methylation of RIZ1 may play an important role in the epigenetic silencing of RIZ1 expression in pituitary adenomas, which may translate into important diagnostic and therapeutic applications.

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

“…Histone methylation and citrullination (conversion of arginine to citrulline catalyzed by peptidylarginine deiminase enzymes) may also mediate tumorigenesis. Enhanced H3K27 methylation and reduced H3K4/H3K9 methylation are found in tumors with increased RIZ1 expression (which is thought to be a histone methyltransferase), which also correlates with longer progression-free survival ( 228 ). Noninvasive tumors also show significantly increased RIZ1 expression compared to invasive tumors ( 228 ).…”

“…Enhanced H3K27 methylation and reduced H3K4/H3K9 methylation are found in tumors with increased RIZ1 expression (which is thought to be a histone methyltransferase), which also correlates with longer progression-free survival ( 228 ). Noninvasive tumors also show significantly increased RIZ1 expression compared to invasive tumors ( 228 ). Citrullination of histone H3 in GH3 cells represses the expression of specific tumor suppressor microRNAs, which leads to increased expression of known drivers such as N-MYC, and IGF-1 and increased proliferation ( 229 ).…”

The Epigenomics of Pituitary Adenoma

“…Non-invasive pituitary adenomas express significantly higher levels of RIZI, which acts as a tumor-suppressor as well as a possible histone methyltransferase, and lower levels of C-myc, as compared to invasive pituitary adenomas (74). Increased RIZI expression also correlates with significant differences in methylation at four CpG sites, reduced H3K4/H3K9 methylation, and enhanced H3K27 methylation, as well as significantly longer progression-free survival (74). Additionally, p53 mis-expression correlates with H3K9 methylation (98).…”

Multifaceted Role of PRDM Proteins in Human Cancer

“…A CpG island in the PRDM2/RIZ1 promoter is frequently methylated in many cancer types, such as breast carcinomas and liver tumors, as well as in colon and lung cancer cell lines [69,70]. Additionally, epigenetic silencing of RIZ1 expression was also detected in pituitary adenomas and nasopharyngeal carcinoma specimens [71,72]. In most of these cases, mutations in PRDM2 gene were not detected [64,65] suggesting that DNA methylation would be the preferred mechanism of RIZ1 inactivation in these malignancies [69].…”