Sp1-mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2-overexpressing breast cancer.
Animals
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Down-Regulation
/ drug effects
Epigenesis, Genetic
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Histone Deacetylase 1
/ genetics
Histone Deacetylase Inhibitors
/ pharmacology
Histone Deacetylases
/ genetics
Humans
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Nude
Promoter Regions, Genetic
/ drug effects
Receptor, ErbB-2
/ genetics
Sp1 Transcription Factor
/ genetics
Transcription, Genetic
/ drug effects
Transcriptional Activation
/ drug effects
Up-Regulation
/ drug effects
Fas
Sp1
histone deacetylation
human epidermal growth factor receptor 2
miR-146a
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
19
12
2018
revised:
23
04
2019
accepted:
13
05
2019
pubmed:
22
5
2019
medline:
31
1
2020
entrez:
22
5
2019
Statut:
ppublish
Résumé
Human epidermal growth factor receptor 2 (HER2/erbB2) is a key driver and therapeutic target for breast cancer. The treatment of HER2-positive breast cancer remains a clinical challenge largely due to the limited understanding of HER2-driving oncogenic signaling and the frequent resistance to simply HER2-targeted therapy. Here, we show that the histone deacetylase inhibitor, trichostatin A (TSA), suppresses HER2-overexpressing breast cancer via upregulation of miR-146a and the resultant repression of its oncogenic targets, interleukin-1 receptor-associated kinase 1 and the chemokine receptor CXCR4. Mechanistically, histone H3K56 acetylation and deacetylation on the MIR146A promoter are catalyzed respectively by the acetyltransferase p300 and histone deacetylase 1 (HDAC1), both of which are recruited to the genomic loci by the transcription factor specificity protein 1 (Sp1). HER2 signaling phosphorylates Sp1 and induces its predominant association with HDAC1, but not p300, leading to histone hypoacetylation and silencing of MIR146A. In addition, the death receptor Fas is similarly downregulated by the aforementioned epigenetic paradigm, indicating its wide involvement in impairing tumor suppressor gene expression. Consequently, TSA synergizes with lapatinib, a tyrosine kinase inhibitor of HER2, to suppress breast cancer in vitro and in rodent models. These findings demonstrate a novel mechanism of HER2-driven carcinogenesis and suggest the applicability of combined HER2 and HDAC targeting in breast cancer therapy.
Substances chimiques
Histone Deacetylase Inhibitors
0
Sp1 Transcription Factor
0
SP1 protein, human
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
HDAC1 protein, human
EC 3.5.1.98
Histone Deacetylase 1
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3285-3298Informations de copyright
© 2019 UICC.
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