J Korean Med Sci.  2015 Aug;30(8):1157-1166. 10.3346/jkms.2015.30.8.1157.

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

• Lee SH
• Lee EH
• Lee SH
• Lee YM
• Kim HD
• Kim YZ

• KMID: 2164512
• DOI: http://doi.org/10.3346/jkms.2015.30.8.1157

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.

Keyword

Atypical Meningioma; Apoptosis; Histone Modification; Recurrence; Epigenetics

MeSH Terms

Adult
Aged
Aged, 80 and over
Apoptosis/*genetics
Apoptosis Regulatory Proteins/genetics
Epigenesis, Genetic/genetics
Female
Gene Expression Regulation, Neoplastic/genetics
Histone Code/genetics
Histone Demethylases/*genetics
Histone-Lysine N-Methyltransferase/*genetics
Humans
Longitudinal Studies
Male
Meningeal Neoplasms/*genetics/pathology
Meningioma/*genetics/pathology
Middle Aged
Neoplasm Recurrence, Local/*genetics
Apoptosis Regulatory Proteins
Histone Demethylases
Histone-Lysine N-Methyltransferase

Figure

• 

  Fig. 1 The immunohistochemical staining findings of the several samples in terms of apoptosis-associated factors and histone 3 lysine methyltransferases and demethylase. (A) Over- and underexpression of CASP3 and BAX, (B) Over- and low expression of survivin and BCL2, (C) Over- and underexpression of UTX and MLL2, (D) Over- and low expression of KDM5c and JMJD5.

• 

  Fig. 2 Unique patterns of immunohistochemical staining between apoptosis-associated factors and histone modifying enzymes. (A) survivin and UTX-MLL2 complex, (B) BCL2 and UTX-MLL2 complex, (C) BAX and KDM5c, (D) CASP3 and JMJD5.

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