TY - JOUR
T1 - Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells
AU - ZAFAR, Anjum
AU - WU, Fan
AU - Hardy, Kristine
AU - Li, Jasmine
AU - TU, Sherry
AU - MCCUAIG, Robert
AU - Harris, Janelle
AU - Khanna, Kum Kum
AU - Attema, Joanne L.
AU - Gregory, Philip
AU - Goodall, Gregory J.
AU - Harrington, Kirsti
AU - Dahlstrom, Jane
AU - BOULDING, Tara Robyn
AU - Madden, Rebecca
AU - Tan, Abel
AU - Milburn, Peter
AU - RAO, Sudha
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
KW - Breast Neoplasms/drug therapy
KW - CD24 Antigen/biosynthesis
KW - Cell Differentiation/genetics
KW - Chromatin/genetics
KW - Chromatin Assembly and Disassembly/genetics
KW - Epithelial-Mesenchymal Transition/genetics
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Hyaluronan Receptors/biosynthesis
KW - Isoenzymes/genetics
KW - MCF-7 Cells
KW - NF-kappa B p50 Subunit/biosynthesis
KW - Neoplasm Invasiveness
KW - Neoplasm Metastasis
KW - Neoplastic Stem Cells/pathology
KW - Protein Kinase C/genetics
KW - Protein Kinase C-theta
KW - RNA Interference
KW - RNA, Messenger/biosynthesis
KW - RNA, Small Interfering
KW - Receptors, Urokinase Plasminogen Activator/genetics
KW - Signal Transduction/genetics
KW - Spheroids, Cellular/pathology
KW - Transcription Factor RelA/biosynthesis
KW - Transforming Growth Factor beta/genetics
UR - http://www.scopus.com/inward/record.url?scp=84904488713&partnerID=8YFLogxK
UR - http://www.mendeley.com/research/chromatinized-protein-kinase-c%CE%B8-directly-regulates-inducible-genes-epithelial-mesenchymal-transition
U2 - 10.1128/MCB.01693-13
DO - 10.1128/MCB.01693-13
M3 - Article
SN - 0270-7306
VL - 34
SP - 2961
EP - 2980
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 16
ER -