Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide in both men and women. Of relevance to our research presented herein are the Transforming growth factor β (TGF-β) signaling pathways and the heat shock response in the context of NSCLC. Dysregulation of TGF-β signaling often results in disease and is a common feature of many cancers including NSCLC where it governs cell fate and epithelial plasticity through the epithelial-to-mesenchymal transition (EMT). Another key feature of oncogenic TGF-β signaling is the crosstalk with other oncogenic pathways, like the NOTCH signaling pathway, which aids to restrict differentiation and modulates proliferation. Our research identified a mechanistic link between histone deacetylase 6 (HDAC6) and TGF-β1-induced Notch1 signaling. When HDAC6 is knocked down with siRNA or its deacetylase function is pharmacologically inhibited TGF-β1 activation of Notch signaling is abrogated. Within this paradigm we identified a protein complex consisting of HDAC6, heat shock protein 90 (HSP90), and the Notch1 receptor. In response to TGF-β1 stimulation, HDAC6 rapidly deacetylates HSP90 at lysine 294 which corresponds with cleavage and activation of Notch1.
Our investigations also uncovered a unique feature of HSP90 function in NSCLC. Activation of the heat shock response triggers activation of Notch1 signaling. We demonstrated that HDAC6 regulates this heat shock-induced Notch1 signaling through modulation of HSP90 function of cytoplasmic sequestration of the key transcription factor that governs the heat shock response, heat shock factor 1 (HSF1). Brief exposure of NSCLC cells to 42°C activates heat shock-induced Notch1 signaling, knockdown of HDAC6 with siRNA or pharmacological inhibition of HDAC6 abrogated this induction. In our investigations employing this combined strategy of targeting both HDAC6 and HSP90 we discovered that this treatment had an additive effect to enhance apoptotic markers and inhibit cell cycle progression in NSCLC cells. Individual HDAC6 or HSP90 inhibition slowed tumorigenesis and enhanced apoptosis of NSCLC in vivo. Taken altogether, our research identifies HDAC6 and HSP90 as regulators of key oncogenic pathways required for EMT and that combined inhibition of both these targets is a rational strategy to selectively kill NSCLC cells.
|Advisor:||Lasky, Joseph A.|
|Commitee:||El-Dahr, Samir, Miller, Charles, Morris, Gilbert, Pociask, Derrick|
|School Location:||United States -- Louisiana|
|Source:||DAI-B 78/08(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Health sciences, Pharmacy sciences|
|Keywords:||Epithelial-to-mesenchymal transition, Heat shock factor 1, Heat shock protein 90, Histone deacetylase 6, Non-small cell lung cancer, Notch1|
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