Abstract
AIM. This study was designed to examine whether the class I and class IIa histone deacetylase (HDAC) inhibitors, sodium butyrate and sodium valproate alter the expression of human NCOR1 and/or NCOR2 genes coding for N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptors), respectively. Human leukemia HL-60 cells were treated for 24 h with 0.5 and 1 mM sodium butyrate, 1 to 3 mM sodium valproate, 1 mcM all-trans retinoic acid (ATRA) or cotreated with 1 mcM ATRA and 0.5 mM sodium butyrate. The acetylation of histones H3 and H4 was analysed by western blotting. The levels of NCOR1 and NCOR2 mRNA were determined by quantitative real-time PCR. Expression of NCF2 gene coding for the NADPH oxidase subunit p67phox was evaluated as a marker of myeloid differentiation. Results. Both butyrate and valproate increased the acetylation of histone H3 at Lys9 and/or Lys14 as well as histone H4 at Lys12. Both HDAC inhibitors caused a significant increase in NCF2 mRNA levels without affecting NCOR1 or NCOR2 mRNA levels. Similarly, ATRA alone or in combination with butyrate induced NCF2 gene expression without any significant influence on the expression of NCOR1 or NCOR2 genes. We conclude that inhibitors of class I and class IIa HDACs do not alter the expression of human NCOR1 or NCOR2 genes and that the onset of myeloid differentiation is not accompanied by induction or repression of these genes in HL-60 cells.
Highlights
Nuclear receptor corepressor (N-CoR) and SMRT are ubiquitously expressed corepressor proteins
Abnormal transcriptional repression resulting from aberrant recruitment of the N-CoR/SMRT-Histone deacetylase (HDAC) complexes appears to underlie the molecular pathogenesis of cancers such as acute promyelocytic leukemia[5]
Since HDAC inhibitors are considered to modulate the expression of 7-10% of genes in human cancer cells[11], we examined whether the expression of human Nuclear receptor corepressor 1 (NCOR1) and/or Nuclear receptor corepressor 2 (NCOR2) genes could be altered by two HDAC inhibitors, sodium butyrate and sodium valproate
Summary
N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptors) are ubiquitously expressed corepressor proteins. They interact with unliganded nuclear receptors and form large corepressor complexes that mediate transcriptional repression through their association with histone deacetylases (HDACs). Unliganded RARα interacts with N-CoR or SMRT which associate through the corepressor mSin[3] (mammalian switch independent 3 protein) with HDAC1 or HDAC2. The corepressor complexes, dissociate from RARα at physiological concentrations of all-trans retinoic acid (ATRA) and subsequent recruitment of coactivators with histone acetylase activity relieves the transcriptional repression of differentiationrelated genes[4]. In accordance with the crucial role of HDACs in corepressor-dependent transcriptional repression, inhibitors of HDAC activity have emerged as a new class of anticancer agents[6]
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