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-theta) promotes EMT by acting as a critical chromatin-anchored switch for inducible genes via transforming growth factor beta (TGF-beta) and the key inflammatory regulatory protein NF-kappaB. Chromatinized PKC-theta 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-theta-sensitive genes that are directly tethered to PKC-theta 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||Zafar, Anjum; Wu, Fan; Hardy, Kristine; Li, J; 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|
|Journal||MOLECULAR AND CELLULAR BIOLOGY|