RT Journal Article
SR Electronic
T1 EMT transcription factor ZEB1 represses the mutagenic POLθ-mediated end-joining pathway in breast cancers
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP canres.2626.2020
DO 10.1158/0008-5472.CAN-20-2626
A1 Prodhomme, Mélanie K.
A1 Pommier, Roxane M.
A1 Franchet, Camille
A1 Fauvet, Frederique
A1 bergoglio, valerie
A1 Brousset, Pierre
A1 Morel, Anne-Pierre
A1 Brunac, Anne-Cecile
A1 Devouassoux-Shisheboran, Mojgan
A1 Petrilli, Virginie
A1 Moyret-Lalle, Caroline
A1 Hoffmann, Jean-Sébastien
A1 Puisieux, Alain
A1 Tissier, Agnès
YR 2020
UL http://cancerres.aacrjournals.org/content/early/2020/11/25/0008-5472.CAN-20-2626.abstract
AB A characteristic of cancer development is the acquisition of genomic instability, which results from the inaccurate repair of DNA damage. Among double-strand break repair mechanisms induced by oncogenic stress, the highly mutagenic theta-mediated end joining (TMEJ) pathway, which requires DNA polymerase theta (POLθ) encoded by the POLQ gene, has been shown to be overexpressed in several human cancers. However, little is known regarding the regulatory mechanisms of TMEJ and the consequence of its dysregulation. In this study, we combine a bioinformatics approach exploring both METABRIC and TCGA databases with CRISPR/Cas9-mediated depletion of the zinc finger E-box binding homeobox 1 (ZEB1) in claudin-low tumor cells or forced expression of ZEB1 in basal-like tumor cells, two triple-negative breast cancer (TNBC) subtypes, to demonstrate that ZEB1 represses POLQ expression. ZEB1, a master EMT inducing-transcription factor, interacted directly with the POLQ promoter. Moreover, downregulation of POLQ by ZEB1 fostered micronuclei formation in TNBC tumor cell lines. Consequently, ZEB1 expression prevented TMEJ activity, with a major impact on genome integrity. In conclusion, we showed that ZEB1 directly inhibits the expression of POLQ and therefore TMEJ activity, controlling both stability and integrity of breast cancer cell genomes.