Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts
✍ Scribed by James S. Chen; Douglas V. Faller
- Book ID
- 102312916
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 407 KB
- Volume
- 202
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Butyrate, a non‐toxic short‐chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti‐tumor agent because it imposes a reversible G~1~ block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti‐proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G~1~ arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin‐dependent kinase inhibitor (CKI) p21^CIP^ are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non‐transformed growth control model. Using murine 3T3 fibroblasts, we find p27^KIP1^ is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21^CIP^, p27^KIP1^ induction did not occur at the transcriptional level; instead, the stability of the p27^KIP1^ protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27^KIP1^ similarly. p27^KIP1^ was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27^KIP1^ is required for the observed G~1~ blockade, as p27^KIP1^‐deficient fibroblasts were resistant to HDAC inhibition‐induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27^KIP1^ in mediating G~1~ arrest in response to these drugs. © 2005 Wiley‐Liss, Inc.