Investigating the lineage-specific roles of the Forkhead box (FOX) family in cancer

Authors

• AV Mitchell
• MM Gottesman

Abstract

The Forkhead box (FOX) superfamily is the largest transcription factor (TF) family in the human genome whose members perform critical functions in development, adult tissue homeostasis, and cancer. Some members drive oncogenesis, offering potential therapeutic targets, while others act as tumor suppressors. Understanding the varied effects of the FOX family across cancer types requires insight into the associated epigenetic mechanisms. Therefore, we hypothesize that comprehensive genomic analysis of cancer cell lines and patient tumor samples can elucidate the contexts in which individual members of the FOX family elicit pro- or anti-tumorigenic effects. In this work, we analyzed data from genome-wide cellular fitness screens (CRISPR-Cas9, RNAi) across human cancer cell lines to identify cellular lineages selectively dependent upon FOX genes. In addition, we analyzed TFs that display a highly correlated pattern of cell dependency with each of the FOX genes to uncover a co-dependency network and their associated functions based on gene expression profiling. We identified ten FOX genes that were selectively essential within a specific cell-type lineage. These lineage-selective FOX genes were found to have co-dependencies, which included other lineage-selective TFs, suggesting a lineage-specific transcriptional network. We also identified several cancer lineages dependent upon multiple members of the FOX family. Patient data validated these findings, linking FOX gene expression to worse overall survival. In lineages dependent upon multiple FOX genes, including sarcoma and lung, elevated expression of both FOX members was associated with the worst survival outcomes. These findings suggest potential cooperation among FOX members in regulating pro-tumorigenic functions.

Scientific Focus Area: Cancer Biology

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