The majority of women diagnosed with
epithelial ovarian cancer eventually develop recurrence, which rapidly evolves into chemoresistant disease. Persistence of
ovarian cancer stem cells (OCSC) at the end of
therapy may be responsible for emergence of resistant
tumors. In this study, we demonstrate that in OCSC, the
tumor suppressor disabled homolog 2-interacting
protein (DAB2IP) is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9-mediated deletion of DAB2IP in
epithelial ovarian cancer cell lines upregulated expression of stemness-related genes and induced conversion of non-CSC to CSC, while enforced expression of DAB2IP suppressed CSC properties. Transcriptomic analysis showed that overexpression of DAB2IP in
ovarian cancer significantly altered stemness-associated genes and bioinformatic analysis revealed WNT signaling as a dominant pathway mediating the CSC inhibitory effect of DAB2IP. Specifically, DAB2IP inhibited WNT signaling via downregulation of WNT5B, an important stemness inducer. Reverse phase
protein array further demonstrated activation of noncanonical WNT signaling via C-JUN as a downstream target of WNT5B, which was blocked by inhibiting RAC1, a prominent regulator of C-JUN activation. Coadministration of EZH2 inhibitor
GSK126 and RAC1 inhibitor
NSC23766 suppressed OCSC survival in vitro and inhibited
tumor growth and increased
platinum sensitivity in vivo. Overall, these data establish that DAB2IP suppresses the cancer stem cell phenotype via inhibition of WNT5B-induced activation of C-JUN and can be epigenetically silenced by EZH2 in OCSC. Targeting the EZH2/DAB2IP/C-JUN axis therefore presents a promising strategy to prevent
ovarian cancer recurrence and has potential for clinical translation. SIGNIFICANCE: These findings show that combining an epigenetic
therapy with a noncanonical WNT signaling pathway inhibitor has the potential to eradicate
ovarian cancer stem cells and to prevent
ovarian cancer recurrence.