Repression of ZNFX1 by LncRNA ZFAS1 mediates tobacco-induced pulmonary carcinogenesis

作者：Sichuan Xi, Jigui Shan, Xinwei Wu, Haitao Wang, Mary R. Zhang, Shakirat Oyetunji, Hong Xu, Zuoxiang Xiao, Tuana Tolunay, Shamus R. Carr, Chuong D. Hoang, David S. Schrump · 发表于：Cellular & Molecular Biology Letters · 年份：2025 · DOI：10.1186/s11658-025-00705-x · 被引用次数：3 · 研究领域：Cancer-related molecular mechanisms research、Genomics and Chromatin Dynamics、RNA Research and Splicing

BACKGROUND: Despite exhaustive research efforts, integrated genetic and epigenetic mechanisms contributing to tobacco-induced initiation and progression of lung cancers have yet to be fully elucidated. In particular, limited information is available regarding dysregulation of noncoding RNAs during pulmonary carcinogenesis. METHODS: We examined correlations and interactions of long noncoding (lnc) RNAs and protein-coding genes in normal respiratory epithelial cells (NREC) and pulmonary tumor cells following exposure to cigarette smoke condensate (CSC) using gene expression arrays, qRT-PCR, western blot, growth assays, transwell assays, and murine xenograft models, as well as methylated DNA immunoprecipitation, RNA cross-link immunoprecipitation, and quantitative chromatin immunoprecipitation techniques with bioinformatics analyses. RESULTS: Among diverse alterations of lncRNA and coding gene expression profiles in NREC exposed to CSC, we observed upregulation of lncRNA ZFAS1 and repression of an adjacent protein-coding gene, ZNFX1, and confirmed these findings in primary lung cancers. Phenotypic experiments indicated that ZFAS1 is an oncogene, whereas ZNFX1 functions as a tumor suppressor in lung cancer cells. Mechanistically, CSC induces ZFAS1 expression via SP1 and NFĸB-associated activation of an enhancer linked to ZFAS1. Subsequently, ZFAS1 interacts with DNA methyltransferases and polycomb group proteins to silence ZNFX1. Mithramycin and methysticin repress ZFAS1 and upre...