Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
Sci Rep. 2018 Jan 8;8(1):73. doi: 10.1038/s41598-017-17913-x.
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.
复杂的调控网络控制上皮-间充质转化（EMT），但其潜在的表观遗传调控机制尚不清楚。赖氨酸特异性去甲基酶 1（LSD1）是一种关键的组蛋白去甲基酶，可改变表观遗传景观。在这里，我们探讨了 LSD1 在 EMT、癌症干细胞（CSCs）、肿瘤微环境和乳腺癌治疗耐药中的全基因组表观遗传调控中的作用。LSD1 在 EMT 和 CSCs 中涉及的网络中诱导全基因组基因表达，并选择性地引发 CSCs 中的基因表达程序，同时抑制非 CSC 程序。由染色质锚定蛋白激酶 C-θ（PKC-θ）磷酸化的 LSD1 丝氨酸 111 位（LSD1-s111p）对于其去甲基酶和 EMT 促进活性至关重要，并且 LSD1-s111p 在体内的耐药细胞中富集。LSD1 与 PKC-θ 结合在间充质基因的表观遗传模板上，促进 LSD1 介导的基因诱导。在体内，化疗可减小肿瘤体积，当与 LSD1 抑制剂联合使用时，可消除间充质特征，并促进先天的、M1 巨噬细胞样肿瘤杀伤免疫反应。转移性乳腺癌（MBC）患者的循环肿瘤细胞（CTC）富含 LSD1，而 LSD1 的药理学阻断可抑制这些患者衍生的 CTC 中的间充质和干细胞样特征。总体而言，LSD1 抑制可能作为一种有前途的表观遗传辅助治疗方法，以颠覆其在乳腺癌进展和治疗耐药中的多效性作用。
