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: 5.81).
10/2010; 67(20):3499-510. DOI: 10.1007/s00018-010-0388-5
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.
Available from: PubMed Central
[Show abstract] [Hide abstract]
ABSTRACT: We investigated the role of HDAC3 in anti-cancer drugresistance. The expression of HDAC3 was decreased in cancer cell lines resistant to anti-cancer drugs such as celastrol and taxol. HDAC3 conferred sensitivity to these anti-cancer drugs. HDAC3 activity was necessary for conferring sensitivity to these anti-cancer drugs. The downregulation of HDAC3 increased the expression of MDR1 and conferred resistance to anti-cancer drugs. The expression of tubulin β3 was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin β3 and HDAC6. HDAC6 showed an interaction with tubulin β3. HDAC3 had a negative regulatory role in the expression of tubulin β3 and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin β3, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin β3 did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin β3 conferred sensitivity to anti-cancer drugs. Our results showed that tubulin β3 serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin β axis can be employed for the development of anti-cancer drugs.
Moleculer Cells 07/2015; 38(8). DOI:10.14348/molcells.2015.0086 · 2.09 Impact Factor
Available from: Dooil Jeoung
- "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). "
[Show abstract] [Hide abstract]
ABSTRACT: Histone acetylation/deacetylation has been known to be associated with the transcriptional regulation of various genes. The role of histone deacetylase-3 in the expression regulation of MDR1 was investigated. The expression level of HDAC3 showed an inverse relationship with the expression level of MDR1. Wild-type HDAC3, but not catalytic mutant HDAC3(S424A), negatively regulated the expression of MDR1. Wild-type HDAC3, but not catalytic mutant HDAC3(S424A), showed binding to the promoter sequences of HDAC3. HDAC3 regulated the expression level and the binding of Ac-H3(K9/14) and Ac-H4(K16) around the MDR1 promoter sequences. The nuclear localization signal domain of HDAC3 was necessary and sufficient for the binding of HDAC3 to the MDR1 promoter sequences and for conferring sensitivity to microtubule-targeting drugs.
BMB reports 12/2013; 47(6). DOI:10.5483/BMBRep.2014.47.6.169 · 2.60 Impact Factor
Available from: Anna Dubrovska
- "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 "
[Show abstract] [Hide abstract]
ABSTRACT: The chemokine CXCL12 (SDF-1) and its cell surface receptor CXCR4 were first identified as regulators of lymphocyte trafficking to the bone marrow. Soon after, the CXCL12/CXCR4 axis was proposed to regulate the trafficking of breast cancer cells to sites of metastasis. More recently, it was established that CXCR4 plays a central role in cancer cell proliferation, invasion, and dissemination in the majority of malignant diseases. The stem cell concept of cancer has revolutionized the understanding of tumorigenesis and cancer treatment. A growing body of evidence indicates that a subset of cancer cells, referred to as cancer stem cells (CSCs), plays a critical role in tumor initiation, metastatic colonization, and resistance to therapy. Although the signals generated by the metastatic niche that regulate CSCs are not yet fully understood, accumulating evidence suggests a key role of the CXCL12/CXCR4 axis. In this review we focus on physiological functions of the CXCL12/CXCR4 signaling pathway and its role in cancer and CSCs, and we discuss the potential for targeting this pathway in cancer management.
OncoTargets and Therapy 09/2013; 6:1347-1361. DOI:10.2147/OTT.S36109 · 2.31 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.