GSE162826
STL427944 suppresses FOXM1 via nuclear export and subsequent autophagic degradation
FOXM1 transcription factor is an oncogene and a crucial regulator of cancer chemoresistance. Existing pharmacological FOXM1 inhibitors attenuate resistance of cancer cells to treatment but exhibit insufficient specificity. We performed in silico screening of small molecules from NIH LINCS database to identify STL427944 compound that suppresses FOXM1 through a novel two-step mechanism. STL427944 treatment induces relocalization of nuclear FOXM1 protein to cytoplasm, where it is subsequently degraded in an autophagosome-dependent manner. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic agents. Transcriptome-based 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 towards FOXM1. We expect that STL427944 or its derivatives may be used in combination with different chemotherapeutical drugs to overcome tumor chemoresistance and improve anti-cancer treatment efficacy. Overall design: For each experimental model and condition, two biological replicates were analyzed. Control samples were treated with vehicle alone (DMSO), with vehicle percentage not exceeding 0.3%.