Metastatic Phosphatase PRL-3 Induces Ovarian Cancer Stem Cell Sub-population through Phosphatase-Independent Deacetylation Modulations

Summary Cancer 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.