title: Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells.
abstract: 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 β (TGF-β) 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.
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Anjum
authors.initials: A
authors.lastname: Zafar
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Hardy
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Li
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Wen Juan
authors.initials: WJ
authors.lastname: Tu
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: McCuaig
authors.affiliation: QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Janelle
authors.initials: J
authors.lastname: Harris
authors.affiliation: QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Attema
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia School of Molecular and Biomedical Science and Department of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: Anatomical Pathology, ACT Pathology, Canberra Hospital, Canberra, Australia.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Anatomical Pathology, ACT Pathology, Canberra Hospital, Canberra, Australia Australian National University Medical School, Canberra, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Dahlstrom
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Tara
authors.initials: T
authors.lastname: Boulding
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Madden
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia.
authors.forename: Abel
authors.initials: A
authors.lastname: Tan
authors.affiliation: ACRF Biomolecular Resource Facility, JCSMR, Australian National University, Canberra, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Milburn
authors.affiliation: Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australia sudha.rao@canberra.edu.au.
authors.forename: Sudha
authors.initials: S
authors.lastname: Rao
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051927:CD24 Antigen / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics*; D061986:MCF-7 Cells; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics*; D000074121:Protein Kinase C-theta; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000473:pathology; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D002843:Chromatin; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D052002:NF-kappa B p50 Subunit; C524898:PLAUR protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta