Expression of TDRD9 in a subset of lung carcinomas by CpG island hypomethylation protects from DNA damage.

Tudor domain containing protein 9 (TDRD9) is a RNA helicase normally expressed in the germline, where it is involved in the biosynthesis of PIWI-interacting RNAs (piRNAs). Here, we show that is highly expressed in a subset of non-small cell lung carcinomas and derived cell lines by hypomethylation of its CpG island. Furthermore, expression is associated with poor prognosis in lung adenocarcinoma. We find that downregulation of expression in TDRD9-positive cell lines causes a decrease in cell proliferation, S-phase cell cycle arrest, and apoptosis. Transcriptomic analysis demonstrated that knockdown causes upregulation of cell cycle and DNA repair genes. We also observed that knockdown triggers activation of the catalytic subunit of the DNA dependent protein kinase (DNA-PKcs) and phosphorylation of H2A.X, which are indicative of an increase of DNA double strand breaks. -silenced cells also presented aberrant mitosis and abnormal-shaped nuclei indicating defects in chromosomal segregation. Finally, silencing caused hypersensitivity to the replication stress inducer aphidicolin, while overexpression of the protein increased resistance to the drug, suggesting that TDRD9 protects from replicative stress to TDRD9-positive tumor cells. Thus, our results place TDRD9 as a marker for prognosis and as a potential therapeutic target in a subset of lung carcinomas.