Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/118275
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Type: Journal article
Title: LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer
Author: Boulding, T.
McCuaig, R.
Tan, A.
Hardy, K.
Wu, F.
Dunn, J.
Kalimutho, M.
Sutton, C.
Forwood, J.
Bert, A.
Goodall, G.
Malik, L.
Yip, D.
Dahlstrom, J.
Zafar, A.
Khanna, K.
Rao, S.
Citation: Scientific Reports, 2018; 8(1):73-1-73-18
Publisher: Springer Nature
Issue Date: 2018
ISSN: 2045-2322
2045-2322
Statement of
Responsibility: 
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
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.
Keywords: Tumor Microenvironment
Rights: © The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
RMID: 0030080537
DOI: 10.1038/s41598-017-17913-x
Grant ID: http://purl.org/au-research/grants/nhmrc/1068065
Appears in Collections:Medicine publications

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