Abstract
SummaryCancer stem cells (CSCs) are responsible for tumor initiation, chemoresistance, metastasis, and relapse, but the underlying molecular origin of CSCs remains elusive. Here we identified that metastatic phosphatase of regenerating liver 3 (PRL-3) transcriptionally upregulates SOX2 in the expansion of CSC sub-population from normal cancer cells. Mechanistically, SOX2 upregulation is attributed to the binding of the acetylated myocyte enhancer factor 2A (MEF2A) to SOX2 promoter in tumor cells. In parallel, PRL-3 competitively binds to Class IIa histone deacetylase 4 (HDAC4) to facilitate HDAC4 translocation, leading to the disassociation of HDAC4 from MEF2A and histones. The released MEF2A and histones thus remain acetylated and render the subsequent accessibility of the acetylated MEF2A to SOX2 promoter region. Clinical relevance among PRL-3, SOX2, and HDAC4 is validated in ovary cancer samples. Therefore, this PRL-3-HDAC4-MEF2A/histones-SOX2 signaling axis would be a potential therapeutic target in inhibiting ovarian cancer metastasis and relapse.
Highlights
Acquisition of extra stem cell-like features by cancer cells greatly limits the clinical utility of most anticancer drugs
Given that epithelialmesenchymal transition (EMT) and PTEN downregulation are important in breast cancer stem cell (CSC) formation and drug resistance (Sun et al, 2016), we suspect that Phosphatase of regenerating liver 3 (PRL-3) may promote the transition of cancer cells to Cancer stem cells (CSCs)
ALDEFLUOR assay showed that aldehyde dehydrogenase (ALDH) activity, a stem-like character, is higher in PRL-3-overexpressing cells than in GFP cells under both adherent condition and the suspension transition state (Figure 1G)
Summary
Acquisition of extra stem cell-like features by cancer cells greatly limits the clinical utility of most anticancer drugs. Recent evidence indicates that the emergence of relapse is unlikely due to all the mutation events in tumor cells (Menon et al, 2015; Sharma et al, 2010), but in part to the occurrence and enrichment of this small sub-population of cancer (stem) cells that is intrinsically heterogeneous and refractory to anti-cancer drugs (Roesch et al, 2013; Trumpp and Wiestler, 2008) This non-mutual scenario proposes that there are non-mutational transition mechanisms under cancer cells to obtain the native or acquired drug tolerance (Ravindran Menon et al, 2015; Sharma et al, 2010; Su et al, 2017). Whether PRL-3 really plays a driving role in CSC formation remains unknown
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