HDAC3 selectively represses CREB3-mediated transcription and migration of metastatic breast cancer cells

Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.86). 10/2010; 67(20):3499-510. DOI: 10.1007/s00018-010-0388-5
Source: PubMed

ABSTRACT We identified CREB3 as a novel HDAC3-interacting protein in a yeast two-hybrid screen for HDAC3-interacting proteins. Among all class I HDACs, CREB3 specifically interacts with HDAC3, in vitro and in vivo. HDAC3 efficiently inhibited CREB3-enhanced NF-κB activation, whereas the other class I HDACs did not alter NF-κB-dependent promoter activities or the expression of NF-κB target genes. Importantly, both knock-down of CREB3 and overexpression of HDAC3 suppressed the transcriptional activation of the novel CREB3-regulated gene, CXCR4. Furthermore, CREB3 was shown to bind to the CRE element in the CXCR4 promoter and to activate the transcription of the CXCR4 gene by causing dissociation of HDAC3 and subsequently increasing histone acetylation. Importantly, both the depletion of HDAC3 and the overexpression of CREB3 substantially increased the migration of MDA-MB-231 metastatic breast cancer cells. Taken together, these findings suggest that HDAC3 selectively represses CREB3-mediated transcriptional activation and chemotactic signalling in human metastatic breast cancer cells.

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    • "HDAC3 regulates the JNK pathway (3), MAPK activation (4), and apoptosis (5). HDAC3 represses CREB3-mediated transcription, and the migration of metastatic breast cancer cells (6). "
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    • "In addition to HIF-1α, some other transcription factors can influence CXCR4 transcription, including v-ets erythroblastosis virus E26 oncogene homolog 1 and NF-kB nuclear factor kappa-light-chain enhancer of activated B cells, which mediate CXCR4-dependent tumor invasion upon stimulation with hepatocyte growth factor.37,120,121 Furthermore, a novel vesnarinone-responsive molecule Krüppel-like factor 2 and histone deacetylase 3-interacting protein CREB3 were also shown to activate the transcription of the CXCR4 and, therefore, contribute to cell migration.122,123 CXCR4 expression and function are positively regulated by the developmental signaling pathways Wnt, SHH and Notch and the oncogenic pathways PI3K/AKT, NF-kB, and JAK/STAT that are also strongly implicated as CSC regulators.124–128 "
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