The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumour cells. The remarkable tumour specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibitors as exciting new agents for the treatment of cancer. The consequence of HDAC inhibition in cultured mammalian cells include reversion of transformed morphology and inhibition of cell proliferation by induction of cell cycle arrest in G1 phase, differentiation and/or apoptosis of tumor cell lines. A number of structurally diverse HDAC inhibitors have been identified, many of which are natural products; among these we have identified 9-hydroxystearic acid (9-HSA), an endogenous long chain lipoperoxidation product (1). We have shown that exposure to 9-HSA results in a significant inhibition of adenocarcinoma colon cancer cells (HT29) proliferation rate, a significant increase of p21 transcription rate, as well as of p21 protein expression level (2). The expression of p21 is induced through a p53-indipendent mechanism, by HDAC1 inhibithion (3). In this work we have isolated histones in order to identify of their acetylation levels, and understand which classes of histones are linked to the 9-HSA induced trancriptional regulation and growth inhibition. Our results have shown that 9-HSA inhibits HDAC activity resulting in the accumulation of acetylated histones. In particular we found that incubation for 6 hours with 9-HSA induced iperacetylation of H4 core histone and H1 linker histone.
9-hydroxystearic acid is a histone deacetylase inhibitor
PAGNOTTA, ELEONORA;CALONGHI, NATALIA;CAPPADONE, CONCETTINA;BOGA, CARLA;MASOTTI, LANFRANCO
2004
Abstract
The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumour cells. The remarkable tumour specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibitors as exciting new agents for the treatment of cancer. The consequence of HDAC inhibition in cultured mammalian cells include reversion of transformed morphology and inhibition of cell proliferation by induction of cell cycle arrest in G1 phase, differentiation and/or apoptosis of tumor cell lines. A number of structurally diverse HDAC inhibitors have been identified, many of which are natural products; among these we have identified 9-hydroxystearic acid (9-HSA), an endogenous long chain lipoperoxidation product (1). We have shown that exposure to 9-HSA results in a significant inhibition of adenocarcinoma colon cancer cells (HT29) proliferation rate, a significant increase of p21 transcription rate, as well as of p21 protein expression level (2). The expression of p21 is induced through a p53-indipendent mechanism, by HDAC1 inhibithion (3). In this work we have isolated histones in order to identify of their acetylation levels, and understand which classes of histones are linked to the 9-HSA induced trancriptional regulation and growth inhibition. Our results have shown that 9-HSA inhibits HDAC activity resulting in the accumulation of acetylated histones. In particular we found that incubation for 6 hours with 9-HSA induced iperacetylation of H4 core histone and H1 linker histone.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
