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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“…Boulding et al showed that CTCs from metastatic breast cancer patients express high levels of LSD1. They observed that EMT can be suppressed using chemical LSD1 blockers, concluding that LSD1 plays a role in EMT and metastasis initiation …”

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“…High LSD1 levels are seen during EMT in MCF‐7 breast cancer cells following stimulation with Phorbol 12‐myristate‐13‐acetate/TGF‐β and in fully dedifferentiated mesenchymal MDA‐MB‐231 breast cancer cells. Decreased LSD1 levels have also been reported during the opposing biological process, mesenchymal‐epithelial transition …”

“…Boulding et al showed that treatment of induced MCF‐7 cells with LSD1 siRNA completely abolished the CD44 + /CD24 − CSC population, and pharmacological inhibition with a known LSD1 inhibitor pargyline partially inhibited CSC formation. In addition, LSD1 inhibition reduced EMT and stemness‐like resistance signatures induced by chemotherapy . In vivo inhibition of LSD1 in combination with chemotherapy reduced tumor growth compared to chemotherapy alone.…”

“…Decreased LSD1 levels have also been reported during the opposing biological process, mesenchymal-epithelial transition. 49 Boulding et al 49 showed that treatment of induced MCF-7 cells with LSD1 siRNA completely abolished the CD44 + /CD24 − CSC population, and pharmacological inhibition with a known LSD1 inhibitor pargyline partially inhibited CSC formation. In addition, LSD1 inhibition reduced EMT and stemness-like resistance signatures induced by chemotherapy.…”

“…In addition, LSD1 inhibition reduced EMT and stemness-like resistance signatures induced by chemotherapy. 49 In vivo inhibition of LSD1 in combination with chemotherapy reduced tumor growth compared to chemotherapy alone. Given these findings, LSD1 inhibitors have the potential to act as anticancer agents in breast cancer due to the pathway's clear role in EMT and CSC formation.…”