The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

Abstract

Ferroptosis, a novel form of regulated cell death, is different from other types of cell death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on cell death linked to cardiomyopathy, tumorigenesis, and cerebral hemorrhage to name a few. Here we summarize current literature on ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming and epigenetic regulators in cancer progression. With regard to organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction and golgi stress-related lipid peroxidation all contribute to induction of ferroptosis. Understanding the underlying mechanism in ferroptosis could provide insight into the treatment of various intractable diseases including cancers.

Keywords: Cancer; Chromatin remodeling factor; Endoplasmic reticulum; Epigenetics; Ferroptosis; Golgi; Immunotherapy; Iron; Lipid peroxidation; Lysosome; Metabolism; Mitochondria; Organelles; lncRNA.

Fig. 1

Known function of organelles in ferroptosis. In the mitochondrion, glutamine is oxidatively phosphorylated, contributing to ROS production. The ER stress response is mediated by the PERK-eIF2α-ATF4 pathway involved in GPX4 degradation, ultimately, inhibiting oxidative injury. In the lysosome, STAT3-mediated cathepsin B expression is required for ferroptosis via the MEK-ERK pathway. Meanwhile, chaperone-mediated autophagy (CMA) regulated by HSP90, CDDO, HSC70 and Lamp-2a promotes the degradation of GPX4. In the Golgi apparatus, Golgi-disrupting compounds enable inhibition of ARF1, an inhibitor of GSH and ACSL4, and activator of SLC7A11, leading to increased ROS

Fig. 2

Metabolic pathways in ferroptosis. In the process of ferroptosis, lipid peroxidation plays a key role in triggering ferroptosis. A great number of molecules participate in ferroptosis by regulating the same protein, resulting in similar downstream pathways. For example, p53, BAP1, ATF3, phosphorylated BECN1,and the combination of erastin and SLC7A5, inhibit expression or activation of SLC7A11, which leads to the depletion of cysteine and GSH in cells. Some other molecules such as FINO2 and RSL3 inhibit GPX4 in cells. The decrease of GSH or GPX4 in cells contributes to lipid peroxidation, ultimately resulting in ferroptosis. MIR137 inhibits SLC1A5 and decreases Gln, Glu, and α-KG in cells, also involved in ferroptosis. The cadherin–NF2–Hippo–YAP signaling axis is involved in ferroptosis. miRNA-17-92 prevents ferroptosis in cells through targeting the A20-ACSL4 axis. ACSL4 that is also regulated by Sp1 regulates the expression of 5-HETE and long polyunsaturated ω6 fatty acids in cells, thus participating in the regulation of ferroptosis

Fig. 3

The epigenetic regulators in ferroptosis. The BAP1-mediated pathway independent of TP53 executes the suppression of SLC7A11. LSH expression is up-regulated by c-Myc, which is enriched at the LSH promoter by the EGLN1-mediated repression of HIF-1α. The induced LSH interacts with WDR76, which, in turn, up-regulates the lipid metabolic genes including SCD1 and FADS2. LSH also induces ELAVL1 expression through the inactivation of p53 and ELAVL1, enhancing LINC00336 levels. LINC00336 serves as an endogenous sponge of MIR6852 as a circulating extracellular DNA (ceRNA), which increases the mRNA levels of CBS, inhibiting ferroptosis in lung cancer. P53RRA promotes ferroptosis by retaining p53 in the nucleus