Chromatinized Protein Kinase C-θ Directly Regulates Inducible Genes in Epithelial to Mesenchymal Transition and Breast Cancer Stem Cells

• Published in: Molecular and cellular biology 2014-08, Vol.34 (16), p.2961-2980
• Main Authors: Zafar, Anjum, Wu, Fan, Hardy, Kristine, Li, Jasmine, Tu, Wen Juan, McCuaig, Robert, Harris, Janelle, Khanna, Kum Kum, Attema, Joanne, Gregory, Philip A., Goodall, Gregory J., Harrington, Kirsti, Dahlstrom, Jane E., Boulding, Tara, Madden, Rebecca, Tan, Abel, Milburn, Peter J., Rao, Sudha
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; CD24 Antigen - biosynthesis; CD24 Antigen - genetics; Cell Differentiation - genetics; Chromatin - genetics; Chromatin Assembly and Disassembly - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors - biosynthesis; Hyaluronan Receptors - genetics; Isoenzymes - genetics; MCF-7 Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells - pathology; NF-kappa B p50 Subunit - biosynthesis; NF-kappa B p50 Subunit - genetics; Protein Kinase C - genetics; Protein Kinase C-theta; Receptors, Urokinase Plasminogen Activator - genetics; RNA Interference; RNA, Messenger - biosynthesis; RNA, Small Interfering; Signal Transduction - genetics; Spheroids, Cellular - pathology; Transcription Factor RelA - biosynthesis; Transcription Factor RelA - genetics; Transforming Growth Factor beta - genetics
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.01693-13

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.