Identification of a functional antioxidant response element at the HIF1A locus

Abstract

Reactive oxygen species (ROS), which are a byproduct of oxidative metabolism, serve as signaling molecules in a number of physiological settings. However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress. Accordingly, several transcriptional regulatory networks have evolved to include components that are highly ROS-responsive. Depending on the context, these regulatory networks can leverage ROS to respond to nutrient conditions, metabolism, or other physiological signals, or to respond to oxidative stress. However, ROS signaling is complex, so regulatory interactions between various ROS-responsive transcription factors are still being mapped out. Here we show that the transcription factor NRF2, a key regulator of the adaptive response to oxidative stress, directly regulates expression of HIF1A, which encodes HIF1α, a key transcriptional regulator of the adaptive response to hypoxia. We used an integrative genomics approach to identify HIF1A as a ROS-responsive transcript and we found an NRF2-bound antioxidant response element (ARE) approximately 30 kilobases upstream of HIF1A. This ARE sequence is deeply conserved, and we verified that it is directly bound and activated by NRF2. In addition, we found that HIF1A is upregulated in breast and bladder tumors with high NRF2 activity. Taken together, our results demonstrate that NRF2 targets a functional ARE at the HIF1A locus, and reveal a direct regulatory connection between two important oxygen responsive transcription factors.

Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy

“…In particular, in accordance with “pathway 1” of Figure 8 , a variety of experimental observations indicate that OS may stimulate HIF-1α stabilization through Nrf2 activation. Indeed, evidence has been obtained in cancer cells that Nrf2 may directly regulate the expression of HIF1A , the gene encoding HIF-1α [ 53 ], while in cardiomyocytes HIF-1α upregulation has been reported to be related to Nrf2 activation through heme oxygenase-1 (HO-1) expression [ 54 ]. The involvement of HO-1 as a mediator of Nrf2 influence on HIF-1α has been confirmed by the observation that HO-1 metabolites, including CO and bilirubin, increased HIF-1α stability in astrocytes [ 55 ].…”

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

“…Conversely, recent evidence suggests that NRF2 also regulates CMA via LAMP2A expression [ 346 ]. In addition, NRF2 directly regulates HIF-1α expression, and interacts with ATF4 [ 347 , 348 ], master regulators of O 2 homeostasis and contributors to autophagy-gene expression (in mild hypoxia, HIF-1 α activates the transcription of mitophagy genes (e.g., NIX ); whereas in severe hypoxia, ATF4 regulates the expression of autophagy genes (e.g., ULK1 and LC3B ) [ 349 , 350 ]). Both, in turn, are regulated by ROS, and act as antioxidant and antiapoptotic proteins [ 351 – 354 ].…”

Hypoxia and HIF Signaling: One Axis with Divergent Effects

“…Several studies focused on the effects of Reactive Oxygen Species (ROS) on HIF-α regulation, highlighting a controversial role depending on the cellular and experimental model. Some evidence indicates that ROS can inhibit PHDs activity, thus increasing HIF1-α stability; however, other evidence supported the role of ROS in inducing the HIF1-α degradation by the ubiquitin proteasome pathway [ 17 , 18 , 19 ].…”