Role of EMT in the DNA damage response, double-strand break repair pathway choice and its implications in cancer treatment

Abstract

Numerous epithelial-mesenchymal transition (EMT) characteristics have now been demonstrated to participate in tumor development. Indeed, EMT is involved in invasion, acquisition of stem cell properties, and therapy-associated resistance of cancer cells. Together, these mechanisms offer advantages in adapting to changes in the tumor microenvironment. However, recent findings have shown that EMT-associated transcription factors (EMT-TFs) may also be involved in DNA repair. A better understanding of the coordination between the DNA repair pathways and the role played by some EMT-TFs in the DNA damage response (DDR) should pave the way for new treatments targeting tumor-specific molecular vulnerabilities, which result in selective destruction of cancer cells. Here we review recent advances, providing novel insights into the role of EMT in the DDR and repair pathways, with a particular focus on the influence of EMT on cellular sensitivity to damage, as well as the implications of these relationships for improving the efficacy of cancer treatments.

Keywords: DNA damage response; DNA repair; ZEB1; epithelial-mesenchymal transition; synthetic lethality.

FIGURE 1

Influence of epithelial to mesenchymal transition (EMT) on the modulation of the DNA repair pathway choice. This schematic representation describes the strong complexity of the modulation of the DNA damage response (DDR) signaling (in gray) as well as the four major DNA double‐strand break repair pathways: c‐NHEJ (in blue), SSA (in yellow), HR (in orange) and TMEJ (in red). This regulation occurs from the DDR signaling, to orientate the repair toward one of these four pathways. Other factors external to the DNA repair pathways (in purple) influence this choice, notably by post‐translational modification (phosphorylation, PARylation, ubiquitination). As shown in this figure, EMT factors (in green) are key modulators of pathways choice

FIGURE 2

Poly(ADP‐ribose)polymerase (PARP) inhibitor‐driven synthetic lethality in the contexts of DNA damage repair deficiencies. PARP inhibitors repress single‐strand break (SSB) repair and base excision repair, as well as TMEJ. While normal cells can repair the resulting double‐strand breaks (DSBs) via the error‐free HR pathway, HR‐deficient cells (e.g., BRCA1/2‐deficient cells) cannot escape from these deleterious effects. In BRCA2‐deficient cells, high dependency on SSA is lethal because this repair system is error prone and causes cell catastrophe. The PARP trapping activity, which is the most marked for talazoparib and the weakest for veliparib, also leads to DNA damage and yields therapeutic efficacies