Adaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species

BACKGROUND AND AIMS: HCC undergoes active metabolic reprogramming. Reactive oxygen species (ROS) arc excessively generated in cancer cells and are neutralized by NADPH. Malic enzymes (MEs) are the less studied NADPH producers in cancer. APPROACH AND RESULTS: We found that ME1, but not ME3, was regulated by the typical oxidative stress response pathway mediated by kelch-like ECH associated protein 1/nuclear factor erythroid 2-related factor (NRF2). Surprisingly, ME3 was constitutively induced by superenhancers. Disruption of any ME regulatory pathways decelerated HCC progression and sensitized HCC to sorafenib. Therapeutically, simultaneous blockade of NRF2 and a superenhancer complex completely impeded HCC growth. We show that superenhancers allow cancer cells to counteract the intrinsically high level of ROS through constitutively activating ME3 expression. When HCC cells encounter further episodes of ROS insult, NRF2 allows cancer cells to adapt by transcriptionally activating MEl. CONCLUSIONS: Our study reveals the complementary regulatory mechanisms which control MEs and provide cancer cells multiple layers of defense against oxidative stress. Targeting both regulatory mechanisms represents a potential therapeutic approach for HCC treatment.

Automated summary

This study reveals the distinct regulatory mechanisms of malic enzymes ME1 and ME3 in hepatocellular carcinoma (HCC), with ME1 being controlled by the NRF2-mediated oxidative stress response pathway and ME3 being constitutively induced by superenhancers. Disrupting these regulatory pathways can slow down HCC progression, and targeting both mechanisms may present a potential therapeutic approach for HCC treatment.