EGFR-induced lncRNA TRIDENT promotes drug resistance in non–small cell lung cancer via phospho-TRIM28-mediated DNA damage repair

Long noncoding RNAs (lncRNAs) play numerous roles in cellular biology and alterations in lncRNA expression profiles have been implicated in a variety of cancers. Here, we identify and characterize a n lncRNA, TRIM28 Interacting DNA damage repair Enhancing Noncoding Transcript (TRIDENT), whose expression is induced upon epithelial growth factor receptor (EGFR) activation, and which exerts pro-oncogenic functions in EGFR-driven non–small cell lung cancer. Knocking down TRIDENT leads to decreased tumor-cell proliferation in both in vitro and in vivo model systems and induces sensitization to chemotherapeutic drugs. Using ChIRP-MS analysis we identified TRIM28 as a protein interactor of TRIDENT. TRIDENT promotes phosphorylation of TRIM28 and knocking down TRIDENT leads to accumulation of DNA damage in cancer cells via decreased TRIM28 phosphorylation. Altogether, our results reveal a molecular pathway in which TRIDENT regulates TRIM28 phosphorylation to promote tumor cell growth and drug resistance. Our findings suggest that TRIDENT can be developed as a biomarker or therapeutic target for EGFR mutant non–small cell lung cancer. RNAseq profiling of H1975-TRE-dCas9-KRAB cells with NT control gRNA, TRIDENT gRNA1 AND TRIDENT gRNA2 after treating with 4ug/ml of doxycycline for 72 hours