LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer

T. Boulding, R. D. McCuaig, A. Tan, K. Hardy, F. Wu, J. Dunn, M. Kalimutho, C. R. Sutton, J. K. Forwood, A. G. Bert, G. J. Goodall, L. Malik, D. Yip, J. E. Dahlstrom, A. Zafar, K. K. Khanna, S. Rao

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22 Citations (Scopus)

Abstract

Complex regulatory networks control epithelial-To-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-Theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

Original languageEnglish
Article number73
Pages (from-to)1-18
Number of pages18
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 8 Jan 2018

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Epithelial-Mesenchymal Transition
Tumor Microenvironment
Lysine
Breast Neoplasms
Epigenomics
Circulating Neoplastic Cells
Neoplastic Stem Cells
Protein Kinase C
Histone Demethylases
Stem Cell Niche
Gene Expression
Tumor Burden
Serine
Genes
Chromatin
Stem Cells
Therapeutics
Macrophages
Phosphorylation

Cite this

Boulding, T. ; McCuaig, R. D. ; Tan, A. ; Hardy, K. ; Wu, F. ; Dunn, J. ; Kalimutho, M. ; Sutton, C. R. ; Forwood, J. K. ; Bert, A. G. ; Goodall, G. J. ; Malik, L. ; Yip, D. ; Dahlstrom, J. E. ; Zafar, A. ; Khanna, K. K. ; Rao, S. / LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer. In: Scientific Reports. 2018 ; Vol. 8. pp. 1-18.
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title = "LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer",
abstract = "Complex regulatory networks control epithelial-To-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-Theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.",
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author = "T. Boulding and McCuaig, {R. D.} and A. Tan and K. Hardy and F. Wu and J. Dunn and M. Kalimutho and Sutton, {C. R.} and Forwood, {J. K.} and Bert, {A. G.} and Goodall, {G. J.} and L. Malik and D. Yip and Dahlstrom, {J. E.} and A. Zafar and Khanna, {K. K.} and S. Rao",
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Boulding, T, McCuaig, RD, Tan, A, Hardy, K, Wu, F, Dunn, J, Kalimutho, M, Sutton, CR, Forwood, JK, Bert, AG, Goodall, GJ, Malik, L, Yip, D, Dahlstrom, JE, Zafar, A, Khanna, KK & Rao, S 2018, 'LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer', Scientific Reports, vol. 8, 73, pp. 1-18. https://doi.org/10.1038/s41598-017-17913-x

LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer. / Boulding, T.; McCuaig, R. D.; Tan, A.; Hardy, K.; Wu, F.; Dunn, J.; Kalimutho, M.; Sutton, C. R.; Forwood, J. K.; Bert, A. G.; Goodall, G. J.; Malik, L.; Yip, D.; Dahlstrom, J. E.; Zafar, A.; Khanna, K. K.; Rao, S.

In: Scientific Reports, Vol. 8, 73, 08.01.2018, p. 1-18.

Research output: Contribution to journalArticle

TY - JOUR

T1 - LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer

AU - Boulding, T.

AU - McCuaig, R. D.

AU - Tan, A.

AU - Hardy, K.

AU - Wu, F.

AU - Dunn, J.

AU - Kalimutho, M.

AU - Sutton, C. R.

AU - Forwood, J. K.

AU - Bert, A. G.

AU - Goodall, G. J.

AU - Malik, L.

AU - Yip, D.

AU - Dahlstrom, J. E.

AU - Zafar, A.

AU - Khanna, K. K.

AU - Rao, S.

PY - 2018/1/8

Y1 - 2018/1/8

N2 - Complex regulatory networks control epithelial-To-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-Theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

AB - Complex regulatory networks control epithelial-To-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-Theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

KW - Biomarkers

KW - Breast Neoplasms/genetics

KW - Cell Line, Tumor

KW - Cell Nucleus/metabolism

KW - Chromatin/genetics

KW - Drug Resistance, Neoplasm/genetics

KW - Epigenesis, Genetic

KW - Epithelial-Mesenchymal Transition/genetics

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Regulatory Networks

KW - Histone Demethylases/genetics

KW - Histones/metabolism

KW - Humans

KW - Neoplastic Stem Cells/metabolism

KW - Phenotype

KW - Protein Transport

KW - Signal Transduction

KW - Transcriptional Activation

KW - Tumor Microenvironment/genetics

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UR - http://www.mendeley.com/research/lsd1-activation-promotes-inducible-emt-programs-modulates-tumour-microenvironment-breast-cancer

U2 - 10.1038/s41598-017-17913-x

DO - 10.1038/s41598-017-17913-x

M3 - Article

VL - 8

SP - 1

EP - 18

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 73

ER -