Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer

Tara Robyn BOULDING, Fan Wu, Robert MCCUAIG, Jenny DUNN, Chris SUTTON, Kris HARDY, Wenjuan Tu, Amanda Bullman, Desmond Yip, Jane Dahlstrom, Sudha RAO

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Abstract

Dual-specificity phosphatases (DUSPs) dephosphorylate threonine/serine and tyrosine residues on their substrates. Here we show that DUSP1, DUSP4, and DUSP6 are involved in epithelial-to-mesenchymal transition (EMT) and breast cancer stem cell (CSC) regulation. DUSP1, DUSP4, and DUSP6 are induced during EMT in a PKC pathway signal-mediated EMT model. We show for the first time that the key chromatin-associated kinase PKC-θ directly regulates a subset of DUSP family members. DUSP1, DUSP4, and DUSP6 globally but differentially co-exist with enhancer and permissive active histone post-translational modifications, suggesting that they play distinct roles in gene regulation in EMT/CSCs. We show that nuclear DUSP4 associates with the key acetyltransferase p300 in the context of the chromatin template and dynamically regulates the interplay between two key phosphorylation marks: the 1834 (active) and 89 (inhibitory) residues central to p300's acetyltransferase activity. Furthermore, knockdown with small-interfering RNAs (siRNAs) shows that DUSP4 is required for maintaining H3K27ac, a mark mediated by p300. DUSP1, DUSP4, and DUSP6 knockdown with siRNAs shows that they participate in the formation of CD44 hi / CD24 lo /EpCAM + breast CSCs: DUSP1 knockdown reduces CSC formation, while DUSP4 and DUSP6 knockdown enhance CSC formation. Moreover, DUSP6 is overexpressed in patient-derived HER2 + breast carcinomas compared to benign mammary tissue. Taken together, these findings illustrate novel pleiotropic roles for DUSP family members in EMT and CSC regulation in breast cancer.

Original languageEnglish
Article numbere0148065
Pages (from-to)1-23
Number of pages23
JournalPLoS One
Volume11
Issue number2
DOIs
Publication statusPublished - 2016

Fingerprint

Dual-Specificity Phosphatases
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Stem cells
Mesenchymal Stromal Cells
breast neoplasms
stem cells
Breast Neoplasms
acetyltransferases
small interfering RNA
Small Interfering RNA
Chromatin
breasts
chromatin
Breast
Phosphorylation
post-translational modification
Threonine
Gene expression
threonine

Cite this

BOULDING, Tara Robyn ; Wu, Fan ; MCCUAIG, Robert ; DUNN, Jenny ; SUTTON, Chris ; HARDY, Kris ; Tu, Wenjuan ; Bullman, Amanda ; Yip, Desmond ; Dahlstrom, Jane ; RAO, Sudha. / Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer. In: PLoS One. 2016 ; Vol. 11, No. 2. pp. 1-23.
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Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer. / BOULDING, Tara Robyn; Wu, Fan; MCCUAIG, Robert; DUNN, Jenny; SUTTON, Chris; HARDY, Kris; Tu, Wenjuan; Bullman, Amanda; Yip, Desmond; Dahlstrom, Jane; RAO, Sudha.

In: PLoS One, Vol. 11, No. 2, e0148065, 2016, p. 1-23.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer

AU - BOULDING, Tara Robyn

AU - Wu, Fan

AU - MCCUAIG, Robert

AU - DUNN, Jenny

AU - SUTTON, Chris

AU - HARDY, Kris

AU - Tu, Wenjuan

AU - Bullman, Amanda

AU - Yip, Desmond

AU - Dahlstrom, Jane

AU - RAO, Sudha

PY - 2016

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AB - Dual-specificity phosphatases (DUSPs) dephosphorylate threonine/serine and tyrosine residues on their substrates. Here we show that DUSP1, DUSP4, and DUSP6 are involved in epithelial-to-mesenchymal transition (EMT) and breast cancer stem cell (CSC) regulation. DUSP1, DUSP4, and DUSP6 are induced during EMT in a PKC pathway signal-mediated EMT model. We show for the first time that the key chromatin-associated kinase PKC-θ directly regulates a subset of DUSP family members. DUSP1, DUSP4, and DUSP6 globally but differentially co-exist with enhancer and permissive active histone post-translational modifications, suggesting that they play distinct roles in gene regulation in EMT/CSCs. We show that nuclear DUSP4 associates with the key acetyltransferase p300 in the context of the chromatin template and dynamically regulates the interplay between two key phosphorylation marks: the 1834 (active) and 89 (inhibitory) residues central to p300's acetyltransferase activity. Furthermore, knockdown with small-interfering RNAs (siRNAs) shows that DUSP4 is required for maintaining H3K27ac, a mark mediated by p300. DUSP1, DUSP4, and DUSP6 knockdown with siRNAs shows that they participate in the formation of CD44 hi / CD24 lo /EpCAM + breast CSCs: DUSP1 knockdown reduces CSC formation, while DUSP4 and DUSP6 knockdown enhance CSC formation. Moreover, DUSP6 is overexpressed in patient-derived HER2 + breast carcinomas compared to benign mammary tissue. Taken together, these findings illustrate novel pleiotropic roles for DUSP family members in EMT and CSC regulation in breast cancer.

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KW - Epithelial-Mesenchymal Transition

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KW - Genetic Loci/genetics

KW - Histones/chemistry

KW - Humans

KW - Lysine/metabolism

KW - MCF-7 Cells

KW - Neoplastic Stem Cells/pathology

KW - Phosphorylation

KW - Protein Kinase C/metabolism

KW - Protein Processing, Post-Translational

KW - Protein Transport

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