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Research Paper|Volume 13, Issue 1|pp 364—375

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

Xin Jin1, Liansheng Gong2, Ying Peng3, Le Li4, Gang Liu2
  • 1Department of Nuclear Medicine, Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
  • 2Department of Biliary Surgery, Xiangya Hospital, Central South University. Changsha 410008, Hunan, China
  • 3Department of International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment and Standards, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
  • 4Hunan Yuantai Biotechnology Co., Ltd, Changsha 410000, Hunan, China
Received: April 28, 2020Accepted: September 5, 2020Published: December 3, 2020
https://doi.org/10.18632/aging.202137

Copyright: © 2020 Jin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.