Epigenetic Role of Histone 3 Lysine Methyltransferase and Demethylase in Regulating Apoptosis Predicting the Recurrence of Atypical Meningioma

Abstract

Alteration of apoptosis is related with progression and recurrence of atypical meningiomas (AMs). However, no comprehensive study has been conducted regarding histone modification regulating apoptosis in AMs. This study aimed to determine the prognostic values of certain apoptosis-associated factors, and examine the role of histone modification on apoptosis in AMs. The medical records of 67 patients with AMs, as diagnosed during recent 13 yr, were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin-embedded tissues for pro-apoptotic factors (CASP3, IGFBP, TRAIL-R1, BAX, and XAF1), anti-apoptotic factors (survivin, ERK, RAF1, MDM2, and BCL2), and the histone modifying enzymes (MLL2, RIZ, EZH1, NSD2, KDM5c, JMJD2a, UTX, and JMJD5). Twenty-six (38.8%) patients recurred during the follow-up period (mean duration 47.7 months). In terms of time-to-recurrence (TTR), overexpression of CASP3, TRAIL-R1, and BAX had a longer TTR than low expression, and overexpression of survivin, MDM2, and BCL2 had a shorter TTR than low expression (P<0.05). Additionally, overexpression of MLL2, UTX, and JMJ5 had shorter TTRs than low expression, and overexpression of KDM5c had a longer TTR than low expression. However, in the multi-variate analysis of predicting factors for recurrence, low expression of CASP3 (P<0.001), and BAX (P<0.001), and overexpression of survivin (P=0.007), and MDM2 (P=0.037) were associated with recurrence independently, but any enzymes modifying histone were not associated with recurrence. Conclusively, this study suggests certain apoptosis-associated factors should be associated with recurrence of AMs, which may be regulated epigenetically by histone modifying enzymes.Graphical Abstract

The anti-apoptotic protein survivin can improve the prognostication of meningioma patients

“…Investigating the survivin expression in 86 atypical and malignant meningiomas, Vranic et al could not prove any association with histopathological grade [ 30 ]. This observation is consistent with the findings of Pfister et al who used a method based on PCR [ 31 ]. Kaoyaselecah et al were able to prove a significant difference in survivin values between benign and malign meningiomas, however, no difference in values was found between benign and atypical meningiomas or between atypical and malign meningiomas [ 45 ].…”

“…We also extended our study to investigate whether survivin expression is associated with RFS and demonstrated that the survivin levels in meningiomas was an independent predictor of RFS. Previous literature has been divided in this area, with one study demonstrating survivin expression as predictive of recurrence free survival (RFS) [ 31 ], while one study showing no such association [ 30 ]. However, this previous negative study measured survivin expression as a score from 1 to 3 based on the approximate percentage of stained cells.…”

“…Few studies have investigated the prognostic value of survivin in meningiomas, showing varying results. While the expression of this biomarker has shown significant correlation with histopathological grade in other brain tumors, including gliomas [ 27 – 29 ], such a correlation has not been proved in meningiomas [ 30 , 31 ]. Only two studies have tried to correlate survivin expression and RFS, demonstrating conflicting results with one study showing a significant association, and one study showing no association [ 30 , 31 ].…”

RETRACTED ARTICLE: Up-regulation of microRNA-497 inhibits the proliferation, migration and invasion but increases the apoptosis of multiple myeloma cells through the MAPK/ERK signaling pathway by targeting Raf-1

“…genes [43][44][45], while Bax is a pro-apoptotic gene [46,47]. There was a positive correlation between the levels of survivin, Bcl-2 and ERK with the antiapoptotic action, while Bax was negatively associated with the levels of survivin and Bcl-2 [48].…”

Atypical and anaplastic meningioma: outcomes in a population based study

“…In one study, authors explored the expression of pro-apoptotic and anti-apoptotic factors in 67 AAM patients, they found that low expression of CASP3 and BAX, and overexpression of survivin and MDM2 were associated with recurrence [33]. Additionally, methylation of PDCD1 and IGF2BP1 was found to correlate with increased malignant potential and associated with an aggressive phenotype [34].…”