LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer
| Autor: | Andrew G. Bert, Anjum Zafar, Gregory J. Goodall, Abel Tan, Christopher Sutton, Jade K. Forwood, Tara Boulding, Kristine Hardy, Robert McCuaig, Laeeq Malik, Murugan Kalimutho, J. Dunn, Jane E. Dahlstrom, Sudha Rao, Desmond Yip, Fan Wu, K. K. Khanna |
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| Přispěvatelé: | 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 |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
animal structures lcsh:Medicine Article 03 medical and health sciences Cancer stem cell medicine Epigenetics lcsh:Science Regulation of gene expression Multidisciplinary biology lcsh:R Mesenchymal stem cell global epigenetic regulation medicine.disease Metastatic breast cancer 3. Good health Chromatin 030104 developmental biology Histone gene expression biology.protein Cancer research Demethylase lcsh:Q epithelial-to-mesenchymal transition (EMT) |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-18 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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