Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

Abstract

Tumor is a local tissue hyperplasia resulted from cancerous transformation of normal cells under the action of various physical, chemical and biological factors. The exploration of tumorigenesis mechanism is crucial for early prevention and treatment of tumors. Epigenetic modification is a common and important modification in cells, including DNA methylation, histone modification, non-coding RNA modification and m6A modification. The normal mode of cell death is programmed by cell death-related genes; however, recent researches have revealed some new modes of cell death, including pyroptosis, ferroptosis, cuproptosis and disulfidptosis. Epigenetic regulation of various cell deaths is mainly involved in the regulation of key cell death proteins and affects cell death by up-regulating or down-regulating the expression levels of key proteins. This study aims to investigate the mechanism of epigenetic modifications regulating pyroptosis, ferroptosis, cuproptosis and disulfidptosis of tumor cells, explore possible triggering factors in tumor development from a microscopic point of view, and provide potential targets for tumor therapy and new perspective for the development of antitumor drugs or combination therapies.

Keywords: Cuproptosis; Disulfidptosis; Epigenetic modification; Ferroptosis; Pyroptosis.

Fig. 1

Classification of epigenetic modifications. Epigenetic modifications are divided into the following main types. First, DNA methylation modification. DNA methylation modification is mainly regulated by two types enzymes involved, tet methylcytosine dioxygenases (TETs), which is responsible for DNA demethylation, and DNA methyltransferases (DNMTs), which is responsible for DNA methylation. Second, m6A modification. m6A modification consists of three enzymes acting in combination with each other. Respectively, eraser: Fat mass and obesity associated (FTO) and AlkB homolog 5, RNA demethylase (ALKBH5). Writer: methyltransferase 3 (METTL3), methyltransferase 14 (METTL14) and so on. Reader: YTH N6-methyladenosine RNA binding protein F1/2/3 (YTHDF1/2/3), YTH N6-methyladenosine RNA binding protein C1/2/3 (YTHDC1/2/3) and insulin like growth factor 2 mRNA binding protein 1/2/3 (IGF2BP1/2/3). Third, histone modification, including histone acetylation, histone methylation, and histone ubiquitination. In addition, there are non-coding RNA modifications, including miRNAs, lncRNAs, and circRNA

Fig. 2

Mechanisms of cellular pyroptosis. Various factors stimulate inflammasomes, which then induce pyroptosis by cleavage of GSDMD and GSDME by the caspase family, releasing IL-18 and IL-1β. LPS Lipopolysaccharide, NLRP1 NLR family pyrin domain containing (1), NLRP3 NLR family pyrin domain containing 3, NLRP4 NLR family pyrin domain containing 4, AIM2 Absent in melanoma (2), PYRIN MEFV innate immunity regulator, pyrin, GSDMD Gasdermin D, GSDME Gasdermin E, IL-18 Interleukin 18, IL-1β Interleukin 1β

Fig. 3

Mechanisms of cellular ferroptosis. Lipid peroxidation is affected when the ferroptosis-activation and ferroptosis-inhibition systems receive a corresponding stimulus. Lipid peroxidation and Fe²⁺ accumulation eventually induce ferroptosis. PUFA-PL: Polyunsaturated fatty acid-containing phospholipid. ACSL4: Acyl-CoA synthetase long chain family member 4. LPCAT3: Lysophosphatidylcholine acyltransferase 3. ALOX: Arachidonate lipoxygenase. POR: Cytochrome p450 oxidoreductase. TFR1 Transferrin receptor, DMT1 Ferrous ion membrane transport protein DMT1, GPX4 Glutathione peroxidase 4, GSH Glutathione, FSP1 Ferroptosis suppressor protein-1, CoQH2 ubiquinol, DHODH Dihydroorotate dehydrogenase, FTH1 Ferritin heavy chain 1 FTL1: Ferritin light polypeptide 1, FPN1 Solute carrier family 40 member 1, SLC7A11 Solute carrier family 7 member 11

Fig. 4

Metabolic processes of Cu + in the human body. Cu⁺ is absorbed in the small intestine, transported to the blood via ATPase copper transporter alpha (ATP7A) and bound to ceruloplasmin (CP), then transferred to the liver via copper transporter 1 (CTR1) and stored in the liver bound to metallothionein (MT), then can be transported to the blood via ATPase copper transport beta (ATP7B) or excreted into the bile

Fig. 5

Mechanisms of cellular disulfidptosis. Glucose starvation and high levels of SLC7A11 resulted in cellular NADPH depletion and cystine accumulation, which further led to F-actin collapse and ultimately induced cellular disulfidptosis. GLUT Glucose transporter, PPP Pentose phosphate pathway, SLC7A11 Solute carrier family 7 member 11, NADPH nicotinamide adenine dinucleotide phosphate. Interconnections between cell death

Fig. 6

Interconnections between cell death. SLC7A11 Solute carrier family 7 member 11, GPX4 glutathione peroxidase 4, GSH Glutathione, BAX BCL2 associated X, apoptosis regulator, TP53 Tumor protein p53