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Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas.

Lucio-Eterovic AK, Cortez MA, Valera ET, Motta FJ, Queiroz RG, Machado HR, Carlotti CG, Neder L, Scrideli CA, Tone LG - BMC Cancer (2008)

Bottom Line: Although considerable progress has been made in the treatment of this aggressive tumor, the clinical outcome for patients remains poor.We found that mRNA levels of class II and IV HDACs were downregulated in glioblastomas compared to low-grade astrocytomas and normal brain tissue (7 in 8 genes, p < 0.05).Additionally, we found that histone H3 (but not histone H4) was more acetylated in glioblastomas than normal brain tissue.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil. abeterov@mdanderson.org

ABSTRACT

Background: Glioblastoma is the most lethal primary malignant brain tumor. Although considerable progress has been made in the treatment of this aggressive tumor, the clinical outcome for patients remains poor. Histone deacetylases (HDACs) are recognized as promising targets for cancer treatment. In the past several years, HDAC inhibitors (HDACis) have been used as radiosensitizers in glioblastoma treatment. However, no study has demonstrated the status of global HDAC expression in gliomas and its possible correlation to the use of HDACis. The purpose of this study was to evaluate and compare mRNA and protein levels of class I, II and IV of HDACs in low grade and high grade astrocytomas and normal brain tissue and to correlate the findings with the malignancy in astrocytomas.

Methods: Forty-three microdissected patient tumor samples were evaluated. The histopathologic diagnoses were 20 low-grade gliomas (13 grade I and 7 grade II) and 23 high-grade gliomas (5 grade III and 18 glioblastomas). Eleven normal cerebral tissue samples were also analyzed (54 total samples analyzed). mRNA expression of class I, II, and IV HDACs was studied by quantitative real-time polymerase chain reaction and normalized to the housekeeping gene beta-glucuronidase. Protein levels were evaluated by western blotting.

Results: We found that mRNA levels of class II and IV HDACs were downregulated in glioblastomas compared to low-grade astrocytomas and normal brain tissue (7 in 8 genes, p < 0.05). The protein levels of class II HDAC9 were also lower in high-grade astrocytomas than in low-grade astrocytomas and normal brain tissue. Additionally, we found that histone H3 (but not histone H4) was more acetylated in glioblastomas than normal brain tissue.

Conclusion: Our study establishes a negative correlation between HDAC gene expression and the glioma grade suggesting that class II and IV HDACs might play an important role in glioma malignancy. Evaluation of histone acetylation levels showed that histone H3 is more acetylated in glioblastomas than normal brain tissue confirming the downregulation of HDAC mRNA in glioblastomas.

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Classification of classes I, II, and IV HDACs by structure and cellular localization.[2,6,44,45].
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Figure 1: Classification of classes I, II, and IV HDACs by structure and cellular localization.[2,6,44,45].

Mentions: Histone deacetylases (HDACs) have recently become recognized as a promising target for cancer therapy, including for the treatment of glioblastomas [2]. Together with histone acetyltransferases (HATs), HDACs are responsible for chromatin packaging, which influences the transcription process. In general, increased levels of acetylation (high HAT levels) are associated with increased transcriptional activity, whereas decreased acetylation levels (high HDAC levels) are associated with repression of transcription (reviewed in [3]). HDACs are classified into 4 major categories based on their homology to yeast HDACs, including structure and cellular localization (Figure 1). Class I and class II HDAC proteins share a common enzymatic mechanism that is the Zn-catalyzed hydrolysis of the acetyl-lysine amide bond. Human class I HDACs includes HDAC1, -2, -3, and -8, which are enzymes similar to the yeast transcriptional regulator Rpd3, generally localized to the nucleus [4,5]. These enzymes are ubiquitously expressed (with the exception of HDAC8, which has higher expression levels in the liver) and seems to function as a complex with other proteins [6]. HDAC1 and -2 only show activity within a protein complex, which consists of proteins necessary for modulating their deacetylase activity and DNA binding, and the recruitment of HDACs to gene promoters [7]. Wilson AJ et al. [8] have suggested that multiple class I HDAC members are also involved in repressing p21 and that the growth inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.


Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas.

Lucio-Eterovic AK, Cortez MA, Valera ET, Motta FJ, Queiroz RG, Machado HR, Carlotti CG, Neder L, Scrideli CA, Tone LG - BMC Cancer (2008)

Classification of classes I, II, and IV HDACs by structure and cellular localization.[2,6,44,45].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2536671&req=5

Figure 1: Classification of classes I, II, and IV HDACs by structure and cellular localization.[2,6,44,45].
Mentions: Histone deacetylases (HDACs) have recently become recognized as a promising target for cancer therapy, including for the treatment of glioblastomas [2]. Together with histone acetyltransferases (HATs), HDACs are responsible for chromatin packaging, which influences the transcription process. In general, increased levels of acetylation (high HAT levels) are associated with increased transcriptional activity, whereas decreased acetylation levels (high HDAC levels) are associated with repression of transcription (reviewed in [3]). HDACs are classified into 4 major categories based on their homology to yeast HDACs, including structure and cellular localization (Figure 1). Class I and class II HDAC proteins share a common enzymatic mechanism that is the Zn-catalyzed hydrolysis of the acetyl-lysine amide bond. Human class I HDACs includes HDAC1, -2, -3, and -8, which are enzymes similar to the yeast transcriptional regulator Rpd3, generally localized to the nucleus [4,5]. These enzymes are ubiquitously expressed (with the exception of HDAC8, which has higher expression levels in the liver) and seems to function as a complex with other proteins [6]. HDAC1 and -2 only show activity within a protein complex, which consists of proteins necessary for modulating their deacetylase activity and DNA binding, and the recruitment of HDACs to gene promoters [7]. Wilson AJ et al. [8] have suggested that multiple class I HDAC members are also involved in repressing p21 and that the growth inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.

Bottom Line: Although considerable progress has been made in the treatment of this aggressive tumor, the clinical outcome for patients remains poor.We found that mRNA levels of class II and IV HDACs were downregulated in glioblastomas compared to low-grade astrocytomas and normal brain tissue (7 in 8 genes, p < 0.05).Additionally, we found that histone H3 (but not histone H4) was more acetylated in glioblastomas than normal brain tissue.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil. abeterov@mdanderson.org

ABSTRACT

Background: Glioblastoma is the most lethal primary malignant brain tumor. Although considerable progress has been made in the treatment of this aggressive tumor, the clinical outcome for patients remains poor. Histone deacetylases (HDACs) are recognized as promising targets for cancer treatment. In the past several years, HDAC inhibitors (HDACis) have been used as radiosensitizers in glioblastoma treatment. However, no study has demonstrated the status of global HDAC expression in gliomas and its possible correlation to the use of HDACis. The purpose of this study was to evaluate and compare mRNA and protein levels of class I, II and IV of HDACs in low grade and high grade astrocytomas and normal brain tissue and to correlate the findings with the malignancy in astrocytomas.

Methods: Forty-three microdissected patient tumor samples were evaluated. The histopathologic diagnoses were 20 low-grade gliomas (13 grade I and 7 grade II) and 23 high-grade gliomas (5 grade III and 18 glioblastomas). Eleven normal cerebral tissue samples were also analyzed (54 total samples analyzed). mRNA expression of class I, II, and IV HDACs was studied by quantitative real-time polymerase chain reaction and normalized to the housekeeping gene beta-glucuronidase. Protein levels were evaluated by western blotting.

Results: We found that mRNA levels of class II and IV HDACs were downregulated in glioblastomas compared to low-grade astrocytomas and normal brain tissue (7 in 8 genes, p < 0.05). The protein levels of class II HDAC9 were also lower in high-grade astrocytomas than in low-grade astrocytomas and normal brain tissue. Additionally, we found that histone H3 (but not histone H4) was more acetylated in glioblastomas than normal brain tissue.

Conclusion: Our study establishes a negative correlation between HDAC gene expression and the glioma grade suggesting that class II and IV HDACs might play an important role in glioma malignancy. Evaluation of histone acetylation levels showed that histone H3 is more acetylated in glioblastomas than normal brain tissue confirming the downregulation of HDAC mRNA in glioblastomas.

Show MeSH
Related in: MedlinePlus