ABSTRACT
Dual-specificity phosphatases (DUSPs) dephosphorylate threonine/serine and tyrosine residues on their substrates. Here we show that DUSP1, DUSP4, and DUSP6 are involved in epithelial-to-mesenchymal transition (EMT) and breast cancer stem cell (CSC) regulation. DUSP1, DUSP4, and DUSP6 are induced during EMT in a PKC pathway signal-mediated EMT model. We show for the first time that the key chromatin-associated kinase PKC-θ directly regulates a subset of DUSP family members. DUSP1, DUSP4, and DUSP6 globally but differentially co-exist with enhancer and permissive active histone post-translational modifications, suggesting that they play distinct roles in gene regulation in EMT/CSCs. We show that nuclear DUSP4 associates with the key acetyltransferase p300 in the context of the chromatin template and dynamically regulates the interplay between two key phosphorylation marks: the 1834 (active) and 89 (inhibitory) residues central to p300's acetyltransferase activity. Furthermore, knockdown with small-interfering RNAs (siRNAs) shows that DUSP4 is required for maintaining H3K27ac, a mark mediated by p300. DUSP1, DUSP4, and DUSP6 knockdown with siRNAs shows that they participate in the formation of CD44hi/CD24lo/EpCAM+ breast CSCs: DUSP1 knockdown reduces CSC formation, while DUSP4 and DUSP6 knockdown enhance CSC formation. Moreover, DUSP6 is overexpressed in patient-derived HER2+ breast carcinomas compared to benign mammary tissue. Taken together, these findings illustrate novel pleiotropic roles for DUSP family members in EMT and CSC regulation in breast cancer.
Subject(s)
Breast Neoplasms/pathology , Dual-Specificity Phosphatases/metabolism , Epithelial-Mesenchymal Transition , Neoplastic Stem Cells/pathology , Biomarkers, Tumor/deficiency , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Chromatin/metabolism , Dual-Specificity Phosphatases/deficiency , Dual-Specificity Phosphatases/genetics , E1A-Associated p300 Protein/metabolism , Epigenomics , Gene Knockdown Techniques , Genetic Loci/genetics , Histones/chemistry , Histones/metabolism , Humans , Lysine/metabolism , MCF-7 Cells , Phosphorylation , Protein Kinase C/metabolism , Protein Processing, Post-Translational , Protein TransportABSTRACT
This paper provides an overview of environmental sustainability in healthcare and highlights the need for a policy framework for action. Examples from overseas demonstrate what has effectively enabled mitigation of and adaptation to the threat of climate change. The need to overcome perceived limits and barriers to health professionals' engagement in sustainable practice is noted. The scientific evidence recommends immediate action.
Subject(s)
Conservation of Natural Resources , Health Care Sector/trends , Australia , Climate Change , Health Policy , Health Services Research , HumansABSTRACT
Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-θ) promotes EMT by acting as a critical chromatin-anchored switch for inducible genes via transforming growth factor ß (TGF-ß) and the key inflammatory regulatory protein NF-κB. Chromatinized PKC-θ exists as an active transcription complex and is required to establish a permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of inducible PKC-θ-sensitive genes that are directly tethered to PKC-θ in the mesenchymal state. Collectively, we show that cross talk between signaling kinases and chromatin is critical for eliciting inducible transcriptional programs that drive mesenchymal differentiation and CSC formation, providing novel mechanisms to target using epigenetic therapy in breast cancer.
