Sp1‐mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2‐overexpressing breast cancer

• Published in: International journal of cancer 2019-12, Vol.145 (12), p.3285-3298
• Main Authors: Li, Guoyin, Xie, Qiaosheng, Yang, Zhiwei, Wang, Lei, Zhang, Xiang, Zuo, Baile, Zhang, Shengli, Yang, Angang, Jia, Lintao
• Format: Article
• Language: English
• Subjects: Acetylation; Acetyltransferase; Animal models; Animals; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer; Carcinogenesis; Cell Line, Tumor; Chemokines; CXCR4 protein; Deacetylation; Down-Regulation - drug effects; Down-Regulation - genetics; Enzyme inhibitors; Epidermal growth factor; Epigenesis, Genetic - genetics; Epigenetics; ErbB-2 protein; Event-related potentials; Fas; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Histone deacetylase; Histone Deacetylase 1 - genetics; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; histone deacetylation; Histones; human epidermal growth factor receptor 2; Humans; Kinases; MCF-7 Cells; Medical research; Mice; Mice, Inbred BALB C; Mice, Nude; miR‐146a; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Protein-tyrosine kinase; Receptor, ErbB-2 - genetics; Sp1; Sp1 protein; Sp1 Transcription Factor - genetics; Therapeutic applications; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Trichostatin A; Tumor suppressor genes; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32425

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. What's new? Signaling through the human epidermal growth factor receptor 2 (HER2) is associated with approximately 20% of breast cancers but the efficacy of anti‐HER2 therapies is severely compromised by drug resistance. Here, the authors uncovered potential benefits of combining anti‐HER2 treatments with inhibitors of histone deacetylases (HDACs). They found HER2 signaling silenced tumor suppressor gene expression by impairing the homeostasis of histone acetylation and manipulating the transcription factor Sp1. These findings offer a new explanation of HER2‐driven carcinogenesis and point to potential benefits of combining HER2‐targeting therapies with HDAC inhibitors.