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

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.

• Authors: Olga Karicheva, José Manuel Rodriguez-Vargas, Nadège Wadier, Kathline Martin-Hernandez, Romain Vauchelles, Najat Magroun, Agnès Tissier, Valérie Schreiber, Françoise Dantzer
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 39 Pg. 64109-64123 (Sep 27 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27579892 (Publication Type: Journal Article, Video-Audio Media)

Chemical References

• Antigens, CD
• CD24 Antigen
• CD24 protein, human
• CD44 protein, human
• CDH1 protein, human
• Cadherins
• Cell Cycle Proteins
• Hyaluronan Receptors
• Octamer Transcription Factor-3
• POU5F1 protein, human
• Reactive Oxygen Species
• SNAI1 protein, human
• SOX2 protein, human
• SOXB1 Transcription Factors
• Snail Family Transcription Factors
• Topoisomerase II Inhibitors
• Transforming Growth Factor beta
• Etoposide
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• PARP3 protein, human
• Poly(ADP-ribose) Polymerases
• GTP-Binding Proteins

Topics

• A549 Cells
• Antigens, CD
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• CD24 Antigen (metabolism)
• Cadherins (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Movement
• Cell Self Renewal
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition (drug effects)
• Etoposide (pharmacology)
• Female
• GTP-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Hyaluronan Receptors (metabolism)
• Mammary Glands, Human (enzymology, pathology)
• Neoplastic Stem Cells (drug effects, enzymology, pathology)
• Octamer Transcription Factor-3 (metabolism)
• Phenotype
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Protein Glutamine gamma Glutamyltransferase 2
• RNA Interference
• Reactive Oxygen Species (metabolism)
• SOXB1 Transcription Factors (metabolism)
• Signal Transduction
• Snail Family Transcription Factors (genetics, metabolism)
• Spheroids, Cellular
• Time Factors
• Topoisomerase II Inhibitors (pharmacology)
• Transfection
• Transforming Growth Factor beta (metabolism)
• Transglutaminases (genetics, metabolism)