title: Differential Roles for DUSP Family Members in Epithelial-to-Mesenchymal Transition and Cancer Stem Cell Regulation in Breast Cancer.
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.
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Tara
authors: T
authors: Boulding
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Fan
authors: F
authors: Wu
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Robert
authors: R
authors: McCuaig
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Jennifer
authors: J
authors: Dunn
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Christopher R
authors: CR
authors: Sutton
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Kristine
authors: K
authors: Hardy
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Wenjuan
authors: W
authors: Tu
authors: Anatomical Pathology, ACT Pathology, The Canberra Hospital, Garran ACT, 2605, Australia.|ANU Medical School, Australian National University, Acton, ACT, 2601, Australia.
authors: Amanda
authors: A
authors: Bullman
authors: ANU Medical School, Australian National University, Acton, ACT, 2601, Australia.|Department of Medical Oncology, The Canberra Hospital, ACT, Garran, 2605 Australia.
authors: Desmond
authors: D
authors: Yip
authors: Anatomical Pathology, ACT Pathology, The Canberra Hospital, Garran ACT, 2605, Australia.|ANU Medical School, Australian National University, Acton, ACT, 2601, Australia.
authors: Jane E
authors: JE
authors: Dahlstrom
authors: Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
authors: Sudha
authors: S
authors: Rao
mesh_terms: D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002843:Chromatin / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D057890:Epigenomics; D058750:Epithelial-Mesenchymal Transition; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000235:genetics; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; D006657:Histones; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D011493:Protein Kinase C; D054637:Dual-Specificity Phosphatases; D008239:Lysine