HDAC3 selectively represses CREB3-mediated transcription and migration of metastatic breast cancer cells.
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.
Kim
Han-Cheon
HC
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.
Choi
Kyung-Chul
KC
Choi
Hyo-Kyoung
HK
Kang
Hee-Bum
HB
Kim
Mi-Jeong
MJ
Lee
Yoo-Hyun
YH
Lee
Ok-Hee
OH
Lee
Jeongmin
J
Kim
Young Jun
YJ
Jun
Woojin
W
Jeong
Jae-Wook
JW
Yoon
Ho-Geun
HG
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
D017362:Cyclic AMP Response Element-Binding Protein; D006655:Histone Deacetylases; D016328:NF-kappa B; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C107941:CREB3 protein, human; C527276:CXCR4 protein, human
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