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Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation.

ABSTRACT: Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.

SUBMITTER: Bekric D

PROVIDER: S-EPMC8998032 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation.

Bekric Dino D Ocker Matthias M Mayr Christian C Stintzing Sebastian S Ritter Markus M Kiesslich Tobias T Neureiter Daniel D

Cancers 20220404 7

Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading caus ...[more]

PMID: 35406596

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Project description:BackgroundRNA 5-methylcytosine (m5C) plays an important role in the progression of hepatocellular carcinoma (HCC). Dysregulation of ferroptosis is closely associated with HCC. However, the effect of the epigenetic mRNA m5C modification on ferroptosis in HCC remains unclear.MethodsIn this study, ferroptosis was evaluated by detecting lipid reactive oxygen species (lipid ROS), ferrous ion and 4-hydroxynonenal (4-HNE) in xenograft mouse model, diethylnitrosamine (DEN)-initiated HCC model and so forth. The regulatory mechanisms of YBX1 in mRNA translation were elucidated using RNA sequencing, ribosome sequencing, RNA immunoprecipitation (RIP)-sequencing, bisulphite sequencing and immunoprecipitation (IP)-mass spectrometry assays. Dual-luciferase reporter, RIP-qPCR, Co-IP, RNA pulldown and methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction (qPCR) assays were performed to validate the mechanism of YBX1 in regulating mRNA translation by m5C modification.ResultsHere, we found that YBX1 promoted the translation of Ring Finger Protein 115 (RNF115) mRNA through m5C modification, thereby inhibiting ferroptosis and promoting HCC development. Moreover, RNF115 was identified as an E3 ubiquitin ligase for dihydroorotate dehydrogenase (DHODH), promoting Lys27 (K27) ubiquitination and inhibiting its autophagic degradation to counteract ferroptosis. In addition, YBX1 bound to the m5C modification sites of RNF115 3'-untranslated region (UTR) and interacted with Eukaryotic Translation Initiation Factor 4A1 (EIF4A1) to bridge the 5'-UTR regions, promoting mRNA circularisation and translation, while NOP2/Sun RNA methyltransferase 2 (NSUN2) was identified as responsible for m5C modification of RNF115 mRNA in HCC.ConclusionsThe current work revealed that YBX1 promoted RNF115 mRNA translation in an m5C-dependent manner, thereby regulating DHODH ubiquitination and expression to suppress ferroptosis. This research sheds light on the mechanism of YBX1 in m5C-modified mRNAs translation and ferroptosis, highlighting its promise as a biomarker for prognosis and a target for therapy in HCC.Key pointsYBX1 inhibits ferroptosis in HCC by regulating the RNF115-DHODH axis. RNF115, an E3 ligase, mediates K27 ubiquitination and autophagic degradation of DHODH. YBX1 binds to the m5C sites of RNF115 mRNA 3'-UTR and interacts with EIF4A1 to bridge the 5'-UTR, promoting mRNA circularisation and translation. High expression of YBX1/RNF115 predicts the poor overall survival in HCC.

Project description:PurposeFerroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC).MethodsThe ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs' expression was further evaluated by quantitative real-time polymerase chain reaction in HCC.ResultsA total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues.ConclusionThese results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

Dataset Information

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation.

Publications

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation.

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