Oncotarget

Research Papers:

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

Olga Karicheva, José Manuel Rodriguez-Vargas, Nadège Wadier, Kathline Martin-Hernandez, Romain Vauchelles, Najat Magroun, Agnès Tissier, Valérie Schreiber and Françoise Dantzer _

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Oncotarget. 2016; 7:64109-64123. https://doi.org/10.18632/oncotarget.11627

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Abstract

Olga Karicheva1, José Manuel Rodriguez-Vargas1, Nadège Wadier1, Kathline Martin-Hernandez1, Romain Vauchelles2, Najat Magroun1, Agnès Tissier3, Valérie Schreiber1, Françoise Dantzer1

1Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d’Excellence Medalis, UMR7242, Centre National de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l’Ecole de Biotechnologie de Strasbourg, 67412 Illkirch, France

2Laboratoire de Biophotonique et Pharmacologie, UMR7213, Centre National de la Recherche Scientifique/Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France

3EMT and Cancer Cell Plasticity, Laboratoire d’Excellence DevWeCan, Equipe labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, F-69008 Lyon, France

Correspondence to:

Françoise Dantzer, email: [email protected]

Keywords: Poly(ADP-ribose) polymerase 3 (PARP3), EMT, TGFβ, ROS, stem cells

Received: April 01, 2016    Accepted: August 10, 2016    Published: August 26, 2016

ABSTRACT

Several members of the Poly(ADP-ribose) polymerase (PARP) family are essential regulators of genome integrity, actively prospected as drug targets for cancer therapy. Among them, PARP3 is well characterized for its functions in double-strand break repair and mitotis. Here we report that PARP3 also plays an integral role in TGFβ and reactive oxygen species (ROS) dependent epithelial-to-mesenchymal transition (EMT) and stem-like cell properties in human mammary epithelial and breast cancer cells. PARP3 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, PARP3 expression is significantly upregulated during TGFβ-induced EMT in various human epithelial cells. In line with this observation, PARP3 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. PARP3 responds to TGFβ-induced ROS to promote a TG2-Snail-E-cadherin axis during EMT. Considering the link between EMT and cancer stem cells, we show that PARP3 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 PARP3 in the control of TGFβ-induced EMT and acquisition of stem-like cell features and further motivate efforts to identify PARP3 specific inhibitors.


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