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

Research output: Contribution to journalArticle

16 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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Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Protein Kinase C
Chromatin
Breast Neoplasms
Genes
Phosphotransferases
Switch Genes
Disease Resistance
Transforming Growth Factors
Eukaryota
Mesenchymal Stromal Cells
Epigenomics
Signal Transduction
Genome
Neoplasm Metastasis
Recurrence
Therapeutics
Neoplasms
Proteins

Cite this

ZAFAR, Anjum ; WU, Fan ; Hardy, Kristine ; Li, Jasmine ; TU, Sherry ; MCCUAIG, Robert ; Harris, Janelle ; Khanna, Kum Kum ; Attema, Joanne L. ; Gregory, Philip ; Goodall, Gregory J. ; Harrington, Kirsti ; Dahlstrom, Jane ; BOULDING, Tara Robyn ; Madden, Rebecca ; Tan, Abel ; Milburn, Peter ; RAO, Sudha. / Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 16. pp. 2961-2980.
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author = "Anjum ZAFAR and Fan WU and Kristine Hardy and Jasmine Li and Sherry TU and Robert MCCUAIG and Janelle Harris and Khanna, {Kum Kum} and Attema, {Joanne L.} and Philip Gregory and Goodall, {Gregory J.} and Kirsti Harrington and Jane Dahlstrom and BOULDING, {Tara Robyn} and Rebecca Madden and Abel Tan and Peter Milburn and Sudha RAO",
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ZAFAR, A, WU, F, Hardy, K, Li, J, TU, S, MCCUAIG, R, Harris, J, Khanna, KK, Attema, JL, Gregory, P, Goodall, GJ, Harrington, K, Dahlstrom, J, BOULDING, TR, 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, vol. 34, no. 16, pp. 2961-2980. https://doi.org/10.1128/MCB.01693-13

Chromatinized protein kinase C-θ directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells. / ZAFAR, Anjum; WU, Fan; Hardy, Kristine; Li, Jasmine; TU, Sherry; MCCUAIG, Robert; Harris, Janelle; Khanna, Kum Kum; Attema, Joanne L.; Gregory, Philip; Goodall, Gregory J.; Harrington, Kirsti; Dahlstrom, Jane; BOULDING, Tara Robyn; Madden, Rebecca; Tan, Abel; Milburn, Peter; RAO, Sudha.

In: Molecular and Cellular Biology, Vol. 34, No. 16, 08.2014, p. 2961-2980.

Research output: Contribution to journalArticle

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

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U2 - 10.1128/MCB.01693-13

DO - 10.1128/MCB.01693-13

M3 - Article

VL - 34

SP - 2961

EP - 2980

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 16

ER -