Zhang Lei, Gatlin Victoria, Gupta Shreyan, Salinas Michael L, Romero Selim, Cai James J, Chapkin Robert S, Safe Stephen
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
Int J Mol Sci. 2025 Apr 21;26(8):3909. doi: 10.3390/ijms26083909.
Bis-indole-derived compounds including 1,1-bis(3'-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) analogs bind both orphan nuclear receptors 4A1 (NR4A1) and NR4A2, and DIM-3,5 compounds act as dual receptor inverse agonists and inhibit both NR4A1- and NR4A2-regulated responses. Chromatin immunoprecipitation assays show that β1-integrin and the methyltransferase gene G9a are regulated by both NR4A1 and NR4A2 acting as cofactors for Sp1- and Sp4-dependent gene expression. DIM-3,5 treatment results in the loss of one or more of these nuclear factors from the β1-integrin and G9a promoters. Single-cell and RNAseq analyses show that both receptors regulate common (<10%) and unique genes in SW480 colon cancer cells; however, functional enrichment analysis of the differentially expressed genes converges to several common pathways and gene ontology terms.
双吲哚衍生化合物，包括1,1 - 双(3'-吲哚基)-1-(3,5 - 二取代苯基)甲烷（DIM - 3,5）类似物，可与孤儿核受体4A1（NR4A1）和NR4A2结合，并且DIM - 3,5化合物作为双受体反向激动剂，抑制NR4A1和NR4A2调节的反应。染色质免疫沉淀分析表明，β1整合素和甲基转移酶基因G9a受NR4A1和NR4A2调控，它们作为Sp1和Sp4依赖性基因表达的辅助因子。DIM - 3,5处理导致这些核因子中的一种或多种从β1整合素和G9a启动子上缺失。单细胞和RNA测序分析表明，这两种受体在SW480结肠癌细胞中调节共同的（<10%）和独特的基因；然而，差异表达基因的功能富集分析汇聚到几个共同的途径和基因本体术语。
