EGFR-induced lncRNA <i>TRIDENT</i> promotes drug resistance in non-small cell lung cancer via phospho-TRIM28-mediated DNA damage repair.

Abstract

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 lncRNA, TRIM28 Interacting DNA damage repair Enhancing Noncoding Transcript (<i>TRIDENT</i>), 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 <i>TRIDENT</i> 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 <i>TRIDENT</i>. <i>TRIDENT</i> promotes phosphorylation of TRIM28 and knocking down <i>TRIDENT</i> leads to accumulation of DNA damage in cancer cells via decreased TRIM28 phosphorylation. Altogether, our results reveal a molecular pathway in which <i>TRIDENT</i> regulates TRIM28 phosphorylation to promote tumor cell growth and drug resistance. Our findings suggest that <i>TRIDENT</i> can be developed as a biomarker or therapeutic target for <i>EGFR</i> mutant non-small cell lung cancer.