Abstract
Dual-specificity phosphatases (DUSPs) dephosphorylate threonine/serine and tyrosine residues on their substrates. Here we show that DUSP1, DUSP4, and DUSP6 are involved in epithelial-to-mesenchymal transition (EMT) and breast cancer stem cell (CSC) regulation. DUSP1, DUSP4, and DUSP6 are induced during EMT in a PKC pathway signal-mediated EMT model. We show for the first time that the key chromatin-associated kinase PKC-θ directly regulates a subset of DUSP family members. DUSP1, DUSP4, and DUSP6 globally but differentially co-exist with enhancer and permissive active histone post-translational modifications, suggesting that they play distinct roles in gene regulation in EMT/CSCs. We show that nuclear DUSP4 associates with the key acetyltransferase p300 in the context of the chromatin template and dynamically regulates the interplay between two key phosphorylation marks: the 1834 (active) and 89 (inhibitory) residues central to p300’s acetyltransferase activity. Furthermore, knockdown with small-interfering RNAs (siRNAs) shows that DUSP4 is required for maintaining H3K27ac, a mark mediated by p300. DUSP1, DUSP4, and DUSP6 knockdown with siRNAs shows that they participate in the formation of CD44hi/CD24lo/EpCAM+ breast CSCs: DUSP1 knockdown reduces CSC formation, while DUSP4 and DUSP6 knockdown enhance CSC formation. Moreover, DUSP6 is overexpressed in patient-derived HER2+ breast carcinomas compared to benign mammary tissue. Taken together, these findings illustrate novel pleiotropic roles for DUSP family members in EMT and CSC regulation in breast cancer.
Highlights
Breast cancer is the most common malignancy in women worldwide [1]
DUSP1 expression was higher in MCF-7 cells, whereas DUSP4 and DUSP6 expression were higher in MDA-MB-231 cells (Fig 1A)
DUSP1 expression was reduced at 24 h and increased and peaked at around 50 h, whereas DUSP4 expression was highly induced and rapidly increased and DUSP6 expression peaked at 24 h declined
Summary
Breast cancer is the most common malignancy in women worldwide [1]. chemotherapy and radiotherapy benefit women and improve patient survival, some cancers are treatment resistant [2]. EMT has been implicated in cancer initiation, progression, metastasis, resistance to conventional therapies, and recurrence [4]. This process is induced via complex interactions between extracellular signals and factors that activate downstream signalling pathways including, but not limited to, the WNT, TGF-β, Notch, Hedgehog, PI3-kinase/AKT, and mitogen-activated protein kinase (MAPK) pathways [5]. These pathways activate EMT-inducing transcription factors (EMT-TFs) such as Snail and Slug, which directly regulate inducible gene expression [6,7]
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