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Histone deacetylase inhibitors as potential anti-skin cancer agents
1Epithelial Pathobiology Group, Centre for Immunology and Cancer Research, University of Queensland Department of Medicine, Princess Alexandra Hospital, Brisbane, Australia. NSaunders@medicine.pa.uq.edu.au
Abstract:
The regulation of squamous differentiation is a tightly regulated process involving transcriptional repression and activation. Previous studies have established that squamous carcinoma cell lines inappropriately regulate the transcription of genes important to the control of squamous differentiation. Histone deactylase inhibitors such as trichostatin A (TSA) and butyrate disrupt normal chromatin structure and cause alterations in gene expression/regulation. For these reasons, we examined the effects of both butyrate and TSA on the growth and differentiation of human keratinocytes or squamous carcinoma cells in tissue culture. We found that treatment of keratinocytes or squamous carcinoma cells with butyrate induced a reversible growth arrest. TSA, on the other hand, induced an irreversible growth arrest in both keratinocytes and squamous carcinoma cells. The growth arrest of keratinocytes induced by TSA or butyrate was accompanied by a reduction in the mRNA levels for proliferation gene cdk1 and an induction of the mRNA for the differentiation-specific transglutaminase type I gene (TG1). In contrast, the squamous carcinoma cells had decreased cdk1 and TG1 mRNA in response to TSA or butyrate. Both of these agents produced transient increases in the acetylation of histone H4 in keratinocytes and squamous carcinoma cells. These data indicated that TSA may have potential as a topical treatment for epidermal malignancies.
Insights
Histone deacetylase inhibitors like trichostatin A (TSA) and butyrate affect squamous cell growth and differentiation. TSA shows potential for treating epidermal malignancies by inducing irreversible growth arrest.
Area of Science:
- Cell Biology
- Molecular Biology
- Dermatology
Background:
- Squamous differentiation is tightly regulated by gene transcription.
- Squamous carcinoma cells exhibit dysregulated gene transcription crucial for differentiation.
- Histone deacetylase inhibitors (HDACi) like trichostatin A (TSA) and butyrate alter chromatin structure and gene expression.
Purpose of the Study:
- To investigate the effects of butyrate and TSA on human keratinocyte and squamous carcinoma cell growth and differentiation.
- To evaluate the potential of TSA as a topical treatment for epidermal malignancies.
Main Methods:
- Treatment of keratinocytes and squamous carcinoma cells with butyrate and TSA in tissue culture.
- Analysis of cell growth arrest and differentiation markers.
- Measurement of mRNA levels for proliferation (cdk1) and differentiation (transglutaminase type I - TG1) genes.
- Assessment of histone H4 acetylation.
Main Results:
- Butyrate induced reversible growth arrest in both cell types.
- TSA induced irreversible growth arrest in both keratinocytes and squamous carcinoma cells.
- In keratinocytes, TSA and butyrate reduced cdk1 mRNA and increased TG1 mRNA.
- In squamous carcinoma cells, TSA and butyrate decreased both cdk1 and TG1 mRNA.
- Both agents caused transient increases in histone H4 acetylation.
Conclusions:
- TSA and butyrate differentially affect gene expression related to proliferation and differentiation in normal and cancerous squamous cells.
- TSA demonstrates potential as a topical therapeutic agent for epidermal malignancies due to its ability to induce irreversible growth arrest.