EGFR-induced lncRNA TRIDENT promotes drug resistance in non-small cell lung cancer via phosphoTRIM28-mediated DNA damage repair
成果类型：
Article
署名作者：
Saxena, Tanvi; Quan, Anan; Chan, Erica; Kozlova, Nina; Matai, Latika; Lee, Jonathan D.; Rupaimoole, Rajesha; Beca, Francisco; Muranen, Taru; Slack, Frank J.
署名单位：
Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Bayer AG; Bayer Healthcare Pharmaceuticals; Merck & Company
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-9916
DOI：
10.1073/pnas.2415389122
发表日期：
2025-03-11
关键词：
long noncoding rnas
epidermal-growth-factor
open platform
kap1
kinase
phosphorylation
biogenesis
mechanisms
substrate
proteins
摘要：
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 (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.