Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification

作者：Rebecca M. Starble, Eric G. Sun, Rana Gbyli, Jonathan S. D. Radda, Jiuwei Lu, Tyler B Jensen, Ning Sun, Nelli Khudaverdyan, Ting Zhao, Bomiao Hu, Mary Ann Melnick, Shuai Zhao, Nitin Roper, Gang Greg Wang, Alan J. Tackett, Yinsheng Wang, Jikui Song, Katerina Politi, Siyuan Wang, Andrew Xiao · 发表于：Nature Structural & Molecular Biology · 年份：2025 · DOI：10.1038/s41594-025-01685-4 · 被引用次数：3 · 研究领域：Epigenetics and DNA Methylation、Histone Deacetylase Inhibitors Research、Cancer-related gene regulation

In mammalian cells, gene copy number is controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, increasing the copy number and expression of tumor-promoting genes and thus promoting cancer progression. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification is frequent. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the underlying mechanisms are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identify a global chromatin-priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading and inter-TAD interactions, which occur before the onset of oncogene amplification. Furthermore, we show that METTL7A, reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. METTL7A appears to remodel the chromatin landscape prior to large-scale copy number gains. Although METTL7A depletion exerts little phenotypical effects on drug-naive cells, its depletion prevents the formation and maintenance of TKI resistant-clones, showcasing its role...