Using RNAi to identify modulators of the HIF pathway/hypoxia for cancer

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2380 As a tumor expands, it outgrows its vasculature, depriving the cells of oxygen and nutrients needed for continued growth and survival. In response to the low oxygen levels, the HIF transcription factors are stabilized, altering the expression of 100’s of genes which coordinately enhance tumor growth. Cancer patients with high levels of tumor HIF expression have a poor prognosis for long-term survival. HIF is a particularly intriguing cancer target in that it is a central node upstream of many pro-cancerous pathways that are currently being individually targeted for cancer therapy. Accordingly, reducing HIF expression may be more efficacious than targeting these pathways individually. To identify genes that modulate the HIF pathway, we conducted a comprehensive genome-scale siRNA screen under hypoxic conditions using a cell-based HIF reporter assay. As part of hit follow-up, we developed several mRNA and protein based cellular and molecular assays to measure HIF pathway activity. From the siRNA screen, we identified ~450 genes that when inhibited decrease the HIF pathway activity to varying extents in a cell context dependent manner. Several of the hits are known HIF modulating genes, validating the method. Other hits appear to be novel HIF modulators. Combining the screening results with network-based analysis should reveal unique insights into how the HIF pathway is regulated.

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