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Histone deacetylase inhibition‐mediated post‐translational elevation of p27 KIP1 protein levels is required for G 1 arrest in fibroblasts
Author(s) -
Chen James S.,
Faller Douglas V.
Publication year - 2005
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20094
Subject(s) - trichostatin a , butyrate , histone deacetylase , chemistry , cell cycle checkpoint , cyclin dependent kinase 2 , cancer research , cell cycle , histone deacetylase 5 , cell culture , microbiology and biotechnology , apoptosis , biology , histone , biochemistry , gene , genetics , fermentation
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.