The Role of Cdo1 in Ferroptosis and Apoptosis in Cancer

Abstract

Cysteine dioxygenase type 1 (Cdo1) is a tumor suppressor gene. It regulates the metabolism of cysteine, thereby influencing the cellular antioxidative capacity. This function puts Cdo1 in a prominent position to promote ferroptosis and apoptosis. Cdo1 promotes ferroptosis mainly by decreasing the amounts of antioxidants, leading to autoperoxidation of the cell membrane through Fenton reaction. Cdo1 promotes apoptosis mainly through the product of cysteine metabolism, taurine, and low level of antioxidants. Many cancers exhibit altered function of Cdo1, underscoring its crucial role in cancer cell survival. Genetic and epigenetic alterations have been found, with methylation of Cdo1 promoter as the most common mutation. The fact that no cancer was found to be caused by altered Cdo1 function alone indicates that the tumor suppressor role of Cdo1 is mild. By compiling the current knowledge about apoptosis, ferroptosis, and the role of Cdo1, this review suggests possibilities for how the mild anticancer role of Cdo1 could be harnessed in new cancer therapies. Here, developing drugs targeting Cdo1 is considered meaningful in neoadjuvant therapies, for example, helping against the development of anti-cancer drug resistance in tumor cells.

Keywords: Cdo1; apoptosis; cancer; cysteine; ferroptosis.

Figure 1

Known pathways protecting cells from ferroptosis. The 3 known pathways involve GPX4 (①), FSP1 (②), and BH4 generated from GCH1 (③), respectively. The 3 pathways have the same effect: protecting the cells from further lipid peroxidation by reducing PLOOH levels. Iron [II/III] reacts with PLOOH via the Fenton reaction to produce free radicals, which can induce the peroxidation of polyunsaturated fatty acids (PUFAs), promoting the loss of membrane integrity and cell death. (GSH: glutathione, GSSG: oxidized glutathione, GPX4: glutathione peroxidase 4, PLOOH: phospholipid hydroperoxide, PLOH: the corresponding alcohol of PLOOH, FSP1: ferroptosis suppressing protein 1, GCH1: GTP cyclohydrolase-1, BH4: tetrahydrobiopterin).

Figure 2

Function of Cdo1 in ferroptosis and targets of Erastin and RSL3 for inducing ferroptosis. Erastin inhibits the cystine/glutamate antiporter by binding to the subunit SLC755A, leading to cysteine deprivation by suppressing cystine uptake and triggering ferroptosis. Similarly, p53 inhibits the synthesis of SLC755A, the subunit of the cystine-glutamate antiporter, suppressing the uptake of cysteine. RSL3 directly binds to GPX4, inhibiting its function. Calcium ions inhibit GPX4 function, too. C-Myb is supposed to regulate Cdo1 expression in ferroptosis by an unknown mechanism. Enzymatic conversion by Cdo1 lowers the cysteine concentration, thereby depleting the pool available for the formation of GSH. Consequently, the autoperoxidation of lipids by the Fenton reaction and PLOOH cannot be inhibited, leading to ferroptosis. (GPX4: glutathione peroxidase 4, PLOOH: phospholipid hydroperoxide, PLOH: the corresponding alcohol of PLOOH, Cdo1: cysteine dioxygenase type 1, GSR: glutathione-disulfide reductase, GSSG: oxidized glutathione, GSH: glutathione, NADPH: triphosphopyridine nucleotide, c-Myb: c-Myb proto-oncogene transcription factor, RSL3: Ras-selective lethal 3).

Figure 3

Percentage of Cdo1 mutations and structural variants in cancers. Overview of cancer types that contain Cdo1 mutations and structural variants. Copy number alterations means the change in the number of copies of a particular region of DNA in the genome, involving either a gain or a loss of copies of a specific DNA segment. Cdo1 mutations appear in nearly every kind of cancer; the figure displays only cancers with a relatively high percentage of Cdo1 genetic variation. Source: CBioportal (2024). Cancers with Cdo1 mutation [Pancancer database] (https://www.cbioportal.org/).

Figure 4

Positions of genetic alterations on Cdo1. This lollipop figure shows the mutated amino acid positions on the Cdo1 protein and the frequency of observation in patients. Source: CBioportal (2024). Types of Cdo1 mutations in cancers [Pancancer database] (https://www.cbioportal.org/).

Figure 5

Theories explaining the methylation of the Cdo1 promoter in cancer. (a) When DNA damage occurs to a tumor suppressor gene, the methylation of the promoter occurs to inhibit the expression of the damaged gene while repairing. When the damaged gene is an anticancer gene, this inhibition can be related to carcinogenesis. In this case, by an unknown mechanism, the methylation of this promoter is not re-exposed in cancer cells for removal. (b) Alternative mechanism for Cdo1 methylation in cancer cells. Cancer cells contain low levels of 5hmC, an element that inhibits the binding of TET and DNMT to the adjacent shore of the unmethylated CpG island. The binding is guided by H3K4me1. In normal cells, the binding of DNMT and TET is largely inhibited by the methylated DNA and 5hmC. Therefore, the unmethylated CpG island is maintained. However, in cancer cells, the 5hmC level is low, H3K4me1 appears at the border directing the binding of DNMT, and TET activity is lost. Only DNMT works on the shore of the island, and the shore is methylated, shortening the island. With a larger portion of the promoter methylated, the expression of Cdo1 is downregulated.

Figure 6

Cdo1 partakes in pathways of ferroptosis and apoptosis. Cdo1 is involved in converting cysteine to taurine, thereby decreasing the cysteine pool for the production of GSH. GSH is a required cofactor of GPX4 that prevents lipid peroxidation. The reduced function of GPX4 allows lipid peroxidation on the cell membrane, ultimately leading to cell death. Upregulated taurine can increase the level of p53, a vital tumor suppressor. Additionally, p53 can induce cell cycle arrest. Lipid peroxidation increases the likelihood of apoptosis and ferroptosis. p53 contributes to ferroptosis by inhibiting the production of the SLC755A, a subunit in the cystine-glutamate antiporter that uptakes cystine.