Abstract
We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition. Moreover WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERα, in a murine xenograft model. Finally, WT161 synergistically enhances bortezomib-induced cytotoxicity, even in bortezomib-resistant breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of breast cancer.
Highlights
Histone proteins are localized in the nuclei of all eukaryotic cells and, as the predominant protein components of chromatin, play a major role in modulating the binding of transcription factors to DNA
Since proliferation of breast cancer cells is mediated by transmembrane growth factor receptors and intracellular hormone/steroid receptors including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3, KIT, estrogen receptor (ER), and progesterone receptor (PGR), we examined the effects of WT161 on receptor mRNA and protein expression
Since we have previously shown that histone deacetylase 6 (HDAC6) inhibitor tubacin selectively induces acetylation of α-tubulin [14], we first examined protein acetylation in MCF7 cells induced by WT161, vorinostat (SAHA), and panobinostat (LBH589) using anti-ac-lysine and anti-ac-α-tubulin Abs
Summary
Histone proteins are localized in the nuclei of all eukaryotic cells and, as the predominant protein components of chromatin, play a major role in modulating the binding of transcription factors to DNA. Acetylation of lysine is regulated by the balance of activities of two key classes of enzymes: histone acetyltransferases (HAT) and histone deacetylases (HDAC). HDAC6 is a class IIB lysine deacetylase which exerts various biologic activities in different cell types www.impactjournals.com/oncotarget [1]. HDAC6 is a critical component of the invasive apparatus of tumor cells [5], and impacts epithelial organization of HER2-positive breast cancer cells [6]. HDAC6 deacetylates HMGN2 to regulate STAT5a activity and breast cancer growth [7]. Patients with HDAC6-positive breast cancer have longer progression-free survival and have increased overall survival after tamoxifen treatment, compared to patients with HDAC6-negative tumors [9]. The biologic significance of HDAC6 in breast cancer has not been fully elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
