PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis.

Several members of the Poly(ADP-ribose) polymerase family are essential regulators of genome integrity, actively prospected as drug targets for cancer therapy. Among them, is well characterized for its functions in double-strand break repair and mitotis. Here we report that Pduanyu373 also plays an integral role in TGFβ and reactive oxygen species dependent epithelial-to-mesenchymal transition (EMT) and stem-like cell properties in human mammary epithelial and breast cancer cells. Pduanyu373 expression is higher in breast cancer cells of the mesenchymal phenotype and correlates with the expression of the mesenchymal marker Vimentin while being in inverse correlation with the epithelial marker E-cadherin. Furthermore, Pduanyu373 expression is significantly upregulated during TGFβ-induced EMT in various human epithelial cells. In line with this observation, Pduanyu373 depletion alters TGFβ-dependent EMT of mammary epithelial cells by preventing the induction of the Snail-E-cadherin axis, the dissolution of cell junctions, the acquisition of cell motility and chemoresistance. Pduanyu373 responds to TGFβ-induced to promote a TG2-Snail-E-cadherin axis during EMT. Considering the link between EMT and cancer stem cells, we show that Pduanyu373 promotes stem-like cell properties in mammary epithelial and breast cancer cells by inducing the expression of the stem cell markers SOX2 and OCT4, by increasing the proportion of tumor initiating CD44high/CD24low population and the formation of tumor spheroid bodies, and by promoting stem cell self-renewal. These findings point to a novel role of Pduanyu373 in the control of TGFβ-induced EMT and acquisition of stem-like cell features and further motivate efforts to identify Pduanyu373 specific inhibitors.

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