Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells

Anjum ZAFAR, Fan WU, Kristine Hardy, Jasmine Li, Sherry TU, Robert MCCUAIG, Janelle Harris, Kum Kum Khanna, Joanne L. Attema, Philip Gregory, Gregory J. Goodall, Kirsti Harrington, Jane Dahlstrom, Tara Robyn BOULDING, Rebecca Madden, Abel Tan, Peter Milburn, Sudha RAO

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17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2961-2980
Number of pages20
JournalMolecular and Cellular Biology
Volume34
Issue number16
DOIs
Publication statusPublished - Aug 2014

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    ZAFAR, A., WU, F., Hardy, K., Li, J., TU, S., MCCUAIG, R., Harris, J., Khanna, K. K., Attema, J. L., Gregory, P., Goodall, G. J., Harrington, K., Dahlstrom, J., BOULDING, T. R., Madden, R., Tan, A., Milburn, P., & RAO, S. (2014). Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells. Molecular and Cellular Biology, 34(16), 2961-2980. https://doi.org/10.1128/MCB.01693-13