TNFSF14/LIGHT, a Non-Canonical NF-kB Stimulus, Induces the HIF Pathway

Non-canonical NF-kB signalling plays important roles in development and function of the immune system but also is deregulated in a number of inflammatory diseases. Although, NF-kB and HIF crosstalk has been documented, this has only been described following canonical NF-kB stimulation, involving RelA/p50 and the HIF-1 dimer. Here we report that the non-canonical inducer TNFSF14/LIGHT leads to HIF induction and activation in cancer cells. We demonstrate that only HIF-2a is induced at the transcriptional level following non-canonical NF-kB activation, via a mechanism dependent on the p52 subunit. Furthermore, we demonstrate that p52 can bind to the HIF-2a gene in cells. These results indicate that non-canonical NF-kB can lead to HIF signalling implicating HIF-2a as one of the downstream effectors of this pathway in cells.