Vulnerability to inhibition of Integrin αv in cancer cells with an activated hypoxic gene expression program

Abstract

Hypoxia-inducible factors (HIFs) that are stabilized in hypoxic stress act as a transcription factor and activate the expression of genes promoting malignant phenotype of cancer. Here, I determined the hypoxia-score, as an indicative of activity of the hypoxic gene expression program, using the gene set variation analysis (GSVA) with a gene set entitled as ‘hallmark hypoxia’. Interrogation of pan-cancer transcriptome data from the cancer genome atlas (TCGA) and cancer cell line encyclopedia (CCLE) revealed that high hypoxia-score associated with poor outcome and resistance to chemotherapies, respectively. Integrative analysis of the hypoxia-scores with a gene dependency dataset which was established by whole-genome scale clustered regularly interspaced short palindromic repeats (CRISPRi) and short hairpin RNA (shRNA) screening with cancer cell lines identified 12 genes (TEAD1, WWTR1, RAC1, PTK2, FERMT2, TLN1, COPG1, ITGAV, TRIO, PPP1R12A, UCF1, KIFC2), as an essential gene in hypoxia-scorehigh cancer cells. Except for genes already implicated in hypoxic signaling pathways and common essential genes, I assessed the effect of gene silencing for four genes (PTK2, UFC1, FERMT2, ITGAV) in hypoxia-scorehigh basal type of breast cancer cell lines. Among those genes, the ablation of ITGAV resulted in a significant and selective anti-proliferative effect in hypoxia-scorehigh cancer cells. Finally, I found that the inhibition of ITGAV causes the elevation of caspase 3/7 activity rather than the attenuation of cell cycle progression. Together, these results propose ITGAV as a potential target for cancers with the activation of hypoxic gene expression program.