- 作者：S.V. Demyanenko ; A.B. Uzdensky ; S.A. Sharifulina ; T.O. Lapteva ; L.P. Polyakova
- 关键词：ALA ; aminolevulinic acid ; AP-1/c-Jun ; activation protein transcription factor 1 ; BACH1 ; breast cancer type1 protein ; CENP-E ; centromere protein E ; hBrm/hsnf2a ; chromatin remodeling factor ; E2F4 ; E2F transcription factor 4 ; FOXC2 ; forkhead box C2 ; G9a ; histone methyltransferase G9a ; hABH1 ; human AlkB homolog 1 ; 纬H2AX ; histone H2AX phosphorylated at serine 139 ; H3K9me2 ; histone H3 dimethylated at lysine 9 ; HDAC-1 ; HDAC-10 and HDAC-11 ; histone deacetylases ; HDRP ; HDAC related protein ; MTA1/MTA1L1
- 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
- 出版年：January, 2014
- 年：2014
- 卷：1840
- 期：1
- 页码：262-270
- 全文大小：1663 K
Background
Photodynamic therapy (PDT) is used for cancer treatment including brain tumors. But the role of epigenetic processes in photodynamic injury of normal brain tissue is unknown.Methods
5-Aminolevulinic acid (ALA), a precursor of protoporphyrin IX (PpIX), was used to photosensitize mouse cerebral cortex. PpIX accumulation in cortical tissue was measured spectrofluorometrically. Hematoxylin/eosin, gallocyanin-chromalum and immunohistochemical staining were used to study morphological changes in PDT-treated cerebral cortex. Proteomic antibody microarrays were used to evaluate expression of 112 proteins involved in epigenetic regulation.
Results
ALA administration induced 2.5-fold increase in the PpIX accumulation in the mouse brain cortex compared to untreated mice. Histological study demonstrated PDT-induced injury of some neurons and cortical vessels. ALA-PDT induced dimethylation of histone H3, upregulation of histone deacetylases HDAC-1 and HDAC-11, and DNA methylation-dependent protein Kaiso that suppressed transcriptional activity. Upregulation of HDAC-1 and H3K9me2 was confirmed immunohistochemically. Down-regulation of transcription factor FOXC2, PABP, and hBrm/hsnf2a negatively regulated transcription. Overexpression of phosphorylated histone H2AX indicated activation of DNA repair, but down-regulation of MTA1/MTA1L1 and PML 鈥?impairment of DNA repair. Overexpression of arginine methyltransferase PRMT5 correlated with up-regulation of transcription factor E2F4 and importin 伪5/7.
Conclusion
ALA-PDT injures and kills some but not all neurons and caused limited microvascular alterations in the mouse cerebral cortex. It alters expression of some proteins involved in epigenetic regulation of transcription, histone modification, DNA repair, nuclear protein import, and proliferation.
General significance
These data indicate epigenetic markers of photo-oxidative injury of normal brain tissue.