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

Abstract

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.

RETRACTED: Hypoxic tumor-derived exosomal circular RNA SETDB1 promotes invasive growth and EMT via the miR-7/Sp1 axis in lung adenocarcinoma

“…46,47 The relative expression of Sp1 in cancer cells in several tumor models, including colon cancer, breast cancers, esophageal carcinomas, and pulmonary cancers, has been shown to be higher than that of neighboring normal tissue. [48][49][50] Previous trials showed that 65% of patients with lung cancer had a greater amount of Sp1 in tumor tissues, 51 and that malignant LUAD cells expressed greater concentrations of Sp1 mRNA and protein relative to ordinary bronchial epithelial cells. 52 Overall, it has been demonstrated that Sp1 contributes to tumorigenesis by controlling growth and proliferationrelated gene transcription.…”

The inhibition of microRNA‐326 by SP1/HDAC1 contributes to proliferation and metastasis of osteosarcoma through promoting SMO expression

“…Sp1 in most cases promotes gene expression; however, miR‐326 was negative regulated by Sp1. Previous study suggested that Sp1 not only functions as a transcription factor, but also participates in epigenetic modification by recruiting HDACs 23,24 . In renal cell carcinoma, loss of the Sp1‐HDAC1 complex is associated with elevated histone H3 acetylation at GM2‐synthase gene promoter, resulting in increased expression of GM2‐synthase and faster proliferation of tumour 23 .…”

CD34 cells in somatic, regenerative and cancer stem cells: Developmental biology, cell therapy, and omics big data perspective

“…In the murine system, transcription factor Sp1 binds to a 39 bp region of CD34 that lies upstream of CD34 transcription initiation start site and increased the promoter activity in hematopoietic cells and in Sp1 null Drosophila S2 cells . Sp1 transcription factor, in fact, gets activated by phosphorylation and reportedly enhances the aggressiveness of breast cancer cells, gliomas, non–small cell lung cancer and pancreatic cancer to name a few. In other words, the binding of SP1 to CD34 promoter or promoters of other genes is associated with enhanced stemness.…”