title: Requirement of HDAC6 for activation of Notch1 by TGF-β1.
abstract: TGF-β1 is enriched in the tumor microenvironment and acts as a key inducer of epithelial to mesenchymal transition (EMT) in lung cancer. The NOTCH signaling pathway is conserved across species and is an essential pathway for development, cell differentiation, and cancer biology. Dysregulation of Notch signaling is a common feature of non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. Crosstalk exists between the NOTCH and TGF-β signaling pathways in EMT. Herein we report that histone deacetylase 6 (HDAC6) modulates TGF-β1-mediated activation of the Notch pathway. HDAC6, a primarily cytoplasmic deacetylase, mediates TGF-β1-induced EMT in human lung cancer cells. Inhibition of HDAC6 with a small molecule inhibitor, namely tubacin or with siRNA attenuated TGF-β1-induced Notch-1 signaling. We show that TGFβ-1-induced EMT is accompanied by rapid HDAC6-dependent deacetylation of heat shock protein 90 (HSP90). Consistently, inhibition of HSP90 with its small molecule inhibitor 17AAG attenuated expression of TGF-β1-induced Notch-1 target genes, HEY-1 and HES-1. These findings reveal a novel function of HDAC6 in EMT via mediating the TGF-β-Notch signaling cascade, and support HDAC6 as a key regulator of TGFβ-induced EMT in NSCLC. This work suggests that HDAC6 may be an attractive therapeutic target against tumor progression and metastasis.
authors: Tulane University Health Sciences Center, Department of Medicine, New Orleans, LA, 70119, USA.
authors: Brian
authors: B
authors: Deskin
authors: Tulane University Health Sciences Center, Department of Medicine, New Orleans, LA, 70119, USA.
authors: Joseph
authors: J
authors: Lasky
authors: Tulane University Health Sciences Center, Department of Medicine, New Orleans, LA, 70119, USA.
authors: Yan
authors: Y
authors: Zhuang
authors: Washington State University-Spokane, Elson S. Floyd College of Medicine, Department of Biomedical Sciences, Spokane, WA, 99210, USA.
authors: Bin
authors: B
authors: Shan
mesh_terms: D000072283:A549 Cells; D000107:Acetylation; D058750:Epithelial-Mesenchymal Transition; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D011499:Protein Processing, Post-Translational; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D053773:Transforming Growth Factor beta1; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6