University of Illinois at Chicago, Department of Medicine, Chicago, IL, USA.
Massachusetts General Hospital, Department of Surgery, Boston, MA, USA.
Cell Death Dis. 2021 Jul 14;12(7):704. doi: 10.1038/s41419-021-03978-0.
FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.
FOXM1 转录因子是一种癌基因，也是多种癌症中化学耐药性的主要调节因子。FOXM1 的药理学抑制作用是一种很有前途的方法，但已被证明具有挑战性。我们进行了网络中心转录组分析，以确定一种新型化合物 STL427944，它通过诱导核 FOXM1 蛋白向细胞质重新定位并促进其随后被自噬体降解，从而选择性地抑制 FOXM1。用 STL427944 处理的人类癌细胞对常规化疗（铂类药物、5-氟尿嘧啶和紫杉烷类）的细胞毒性作用更敏感。STL427944 诱导的基因表达变化的 RNA-seq 分析显示，FOXM1 及其下游靶标特征基因的显著抑制，但其他重要调控途径没有明显变化，这表明 STL427944 对 FOXM1 途径具有很高的选择性。总的来说，STL427944 通过自噬依赖性方式抑制 FOXM1 的新机制验证了一种独特的途径，可以克服肿瘤的化学耐药性，并提高常规癌症药物治疗的疗效。
