Enhancer-bound Nrf2 licenses HIF-1α transcription under hypoxia to promote cisplatin resistance in hepatocellular carcinoma cells.

Tumor microenvironment is hypoxic, which can cause resistance to chemotherapy, but the detailed mechanisms remain elusive. Here we find that mild hypoxia (5% O2) further increases cisplatin resistance in the already resistant HepG2/DDP but not the sensitive HepG2 cells. We find that Nrf2 is responsible for cisplatin resistance under hypoxia, as Nrf2 knockdown sensitizes HepG2/DDP cells while Nrf2 hyper-activation (though KEAP1 knockdown) increases resistance of HepG2 cells to cisplatin. Nrf2 binds to an enhancer element in the upstream of HIF-1α gene independently of hypoxia, promoting HIF-1α mRNA synthesis under hypoxic condition. As a result, Nrf2-dependent transcription counteracts HIF-1α degradation under mild hypoxia condition, leading to preferential cisplatin-resistance in HepG2/DDP cells. Our data suggest that Nrf2 regulation of HIF-1α could be an important mechanism for chemotherapy resistance in vivo.