Abstract
Differential positioning of the histone variant H2A.Z in a p53 dependent manner was shown to regulate p21 transcription. Whether H2A.Z is involved in p21 activity in the absence of p53 is not known. The p21 gene is repressed in estrogen receptor (ER) negative cell lines that are p53−/− and hormone independent for their growth. Here we demonstrate that class I and II pan Histone deacetylase inhibitors (HDACi) induce p21 transcription and reduce cell proliferation of MDA-MB231, an ERα-negative mammary tumor cell line, in a H2A.Z dependent manner. H2A.Z is associated with the transcription start site (TSS) of the repressed p21 gene. Depleting H2A.Z did not lead to transcription of p21 but annihilated the stimulating effect of HDACi on this gene. Acetylation of H2A.Z but not of H3K9 at the p21 promoter correlated with p21 activation. We further show that HDACi treatment reduced the presence of the p400 chromatin remodeler at the p21 TSS. We propose a model in which association of p400 negatively affects p21 transcription by interfering with acetylation of H2A.Z.
Highlights
Estrogen receptor negative breast cancer types are generally more aggressive and prone to metastasize
As previously described for pan Histone deacetylase inhibitors (HDACi) [21,22,23] p21 transcription was greatly activated in cells exposed to Trichostatin A (TSA) for 24 h in which we detected .3-fold increase in p21 mRNA levels (Fig. 1b) and a massive augmentation in p21 protein expression compared to untreated cells (Fig. 1c, S1d)
We propose that acetylation of H2A.Z rather than its presence correlates with p21 transcription activation in Estrogen receptor-alpha (ERa)- breast cancers
Summary
Estrogen receptor negative breast cancer types are generally more aggressive and prone to metastasize. The absence of Estrogen receptor-alpha (ERa) correlates with hormone-independent growth of these mammary tumor cells and causes uncontrolled proliferation and insensitivity to anti-hormonal treatments. In ERa-negative cell lines, a subset of genes is epigenetically silenced [1,2], while the majority of genes involved in cell cycle control and proliferation are constitutively expressed [1,3,4]. Histone deacetylase (HDAC) inhibitors, such as Trichostatin A (TSA), Suberoylanilide hydroxamic acid (SAHA), Panobinostat (LBH598) and sodium butyrate (NaB) can inhibit cancer cell growth in vitro and in vivo [10,11,12] as a result of selective induction of endogenous genes that play significant roles in G1-S progression [5]. One of the major regulators of cell cycle progression is the cyclin-dependent kinase inhibitor p21 CIP1/WAF1, a gene of the CIP/KIP family, which inhibits CDK activity. Activation of p21 involves acetylation of promoter chromatin, but the mechanism remains poorly understood [13,14]
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