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Sp1‐mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2‐overexpressing breast cancer
Author(s) -
Li Guoyin,
Xie Qiaosheng,
Yang Zhiwei,
Wang Lei,
Zhang Xiang,
Zuo Baile,
Zhang Shengli,
Yang Angang,
Jia Lintao
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32425
Subject(s) - cancer research , trichostatin a , histone deacetylase , biology , lapatinib , histone deacetylase 2 , histone deacetylase inhibitor , cancer epigenetics , histone deacetylase 5 , breast cancer , epigenetics , cancer , histone methyltransferase , histone , trastuzumab , genetics , gene
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.