Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

ABSTRACT: Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Using genetic tools, including extensive bioinformatics analysis coupled with CRISPR/Cas9 technologies, we have validated GSTO1 as an impactful target in oncology. Through transcriptional profiling using Bru-seq and RNA-seq coupled with proteomics, we uncovered novel pharmacodynamic markers and cellular pathways regulated by GSTO1. Our CRISPR/Cas9 GSTO1 knockout (KO) cell lines do not form tumors or display growth delay in vivo and form smaller 3D spheroids in vitro. Through multi-omics studies in GSTO1 KO cells, we found a strong positive correlation with cell adhesion molecules and interferon response pathways, and a strong negative correlation with Myc transcriptional signature. Importantly, we also identified several clinically used drugs showing significant synthetic lethality with loss or inhibition of GSTO1. We discovered that tissue factor (gene name, F3) transcription and protein expression are downregulated in response to GSTO1 KO. Associated with poor patient survival and promotion of tumor progression in multiple cancers, F3 is a known risk factor for metastasis. F3 transcription is under the regulation of IL-1β, whose secretion is decreased upon GSTO1 inhibition, suggesting that IL-1β links GSTO1 expression and F3 transcription. In summary, our results implicate GSTO1 as a therapeutic target in cancer and offer new mechanistic insights into its significant role in cancer progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147626 | GEO | 2020/09/16

REPOSITORIES: GEO