Division of Reproductive Sciences in Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sci Adv. 2022 Apr 29;8(17):eabh3635. doi: 10.1126/sciadv.abh3635. Epub 2022 Apr 27.
MYC regulates multiple gene programs, raising questions about the potential selectivity and downstream transcriptional consequences of MYC inhibitors as cancer therapeutics. Here, we examined the effect of a small-molecule MYC inhibitor, MYCi975, on the MYC/MAX cistromes, epigenome, transcriptome, and tumorigenesis. Integrating these data revealed three major classes of MYCi975-modulated gene targets: type 1 (down-regulated), type 2 (up-regulated), and type 3 (unaltered). While cell cycle and signal transduction pathways were heavily targeted by MYCi, RNA biogenesis and core transcriptional pathway genes were spared. MYCi975 altered chromatin binding of MYC and the MYC network family proteins, and chromatin accessibility and H3K27 acetylation alterations revealed MYCi975 suppression of MYC-regulated lineage factors AR/ARv7, FOXA1, and FOXM1. Consequently, MYCi975 synergistically sensitized resistant prostate cancer cells to enzalutamide and estrogen receptor-positive breast cancer cells to 4-hydroxytamoxifen. Our results demonstrate that MYCi975 selectively inhibits MYC target gene expression and provide a mechanistic rationale for potential combination therapies.
MYC 调节多个基因程序，这使得人们对 MYC 抑制剂作为癌症治疗药物的潜在选择性和下游转录后果产生了疑问。在这里，我们研究了一种小分子 MYC 抑制剂 MYCi975 对 MYC/MAX 顺式作用元件、表观基因组、转录组和肿瘤发生的影响。整合这些数据揭示了 MYCi975 调节的基因靶标有三大类：1 型（下调）、2 型（上调）和 3 型（未改变）。虽然 MYCi 靶向细胞周期和信号转导途径，但 RNA 生物发生和核心转录途径基因则未受影响。MYCi975 改变了 MYC 和 MYC 网络家族蛋白的染色质结合，并且染色质可及性和 H3K27 乙酰化的改变表明 MYCi975 抑制了 MYC 调节的谱系因子 AR/ARv7、FOXA1 和 FOXM1。因此，MYCi975 协同增强了对恩杂鲁胺有抗性的前列腺癌细胞和对 4-羟基他莫昔芬有抗性的雌激素受体阳性乳腺癌细胞的敏感性。我们的结果表明，MYCi975 选择性地抑制了 MYC 靶基因的表达，并为潜在的联合治疗提供了机制上的依据。
