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Epigenetic Regulation of Ferroptosis-Associated Genes and Its Implication in Cancer Therapy.

ABSTRACT: Ferroptosis is an evolutionarily conserved form of regulated cell death triggered by iron-dependent phospholipid peroxidation. Ferroptosis contributes to the maintenance of tissue homeostasis under physiological conditions while its aberration is tightly connected with lots of pathophysiological processes such as acute tissue injury, chronic degenerative disease, and tumorigenesis. Epigenetic regulation controls chromatin structure and gene expression by writing/reading/erasing the covalent modifications on DNA, histone, and RNA, without altering the DNA sequence. Accumulating evidences suggest that epigenetic regulation is involved in the determination of cellular vulnerability to ferroptosis. Here, we summarize the recent advances on the epigenetic mechanisms that control the expression of ferroptosis-associated genes and thereby the ferroptosis process. Moreover, the potential value of epigenetic drugs in targeting or synergizing ferroptosis during cancer therapy is also discussed.

SUBMITTER: Pei Y

PROVIDER: S-EPMC8841808 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Epigenetic Regulation of Ferroptosis-Associated Genes and Its Implication in Cancer Therapy.

Pei Yanzi Y Qian Yujie Y Wang Hao H Tan Li L

Frontiers in oncology 20220131

Ferroptosis is an evolutionarily conserved form of regulated cell death triggered by iron-dependent phospholipid peroxidation. Ferroptosis contributes to the maintenance of tissue homeostasis under physiological conditions while its aberration is tightly connected with lots of pathophysiological processes such as acute tissue injury, chronic degenerative disease, and tumorigenesis. Epigenetic regulation controls chromatin structure and gene expression by writing/reading/erasing the covalent modi ...[more]

PMID: 35174081

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Project description:BackgroundIn an effort to contribute to overcoming the platinum resistance exhibited by most solid tumors, we performed an array of epigenetic approaches, integrating next-generation methodologies and public clinical data to identify new potential epi-biomarkers in ovarian cancer, which is considered the most devastating of gynecological malignancies.MethodsWe cross-analyzed data from methylome assessments and restoration of gene expression through microarray expression in a panel of four paired cisplatin-sensitive/cisplatin-resistant ovarian cancer cell lines, along with publicly available clinical data from selected individuals representing the state of chemoresistance. We validated the methylation state and expression levels of candidate genes in each cellular phenotype through Sanger sequencing and reverse transcription polymerase chain reaction, respectively. We tested the biological role of selected targets using an ectopic expression plasmid assay in the sensitive/resistant tumor cell lines, assessing the cell viability in the transfected groups. Epigenetic features were also assessed in 189 primary samples obtained from ovarian tumors and controls.ResultsWe identified PAX9 and FKBP1B as potential candidate genes, which exhibited epigenetic patterns of expression regulation in the experimental approach. Re-establishment of FKBP1B expression in the resistant OVCAR3 phenotype in which this gene is hypermethylated and inhibited allowed it to achieve a degree of platinum sensitivity similar to the sensitive phenotype. The evaluation of these genes at a translational level revealed that PAX9 hypermethylation leads to a poorer prognosis in terms of overall survival. We also set a precedent for establishing a common epigenetic signature in which the validation of a single candidate, MEST, proved the accuracy of our computational pipelines.ConclusionsEpigenetic regulation of PAX9 and FKBP1B genes shows that methylation in non-promoter areas has the potential to control gene expression and thus biological consequences, such as the loss of platinum sensitivity. At the translational level, PAX9 behaves as a predictor of chemotherapy response to platinum in patients with ovarian cancer. This study revealed the importance of the transcript-specific study of each gene under potential epigenetic regulation, which would favor the identification of new markers capable of predicting each patient's progression and therapeutic response.

Project description:Background: In order to reveal the functions of ferroptosis in prostate cancer (PCa), a ferroptosis potential index (FPI) was built. This study researched the influence of ferroptosis on gene mutations, various cellular signaling pathways, biochemical recurrence (BCR), and drug resistance in both FPI-high and FPI-low groups. Methods: RNA-seq, somatic mutation data, and clinical data were obtained from The Cancer Genome Atlas (TCGA). FPI values were calculated. All samples were divided into FPI-high and FPI-low groups. The BCR-free survival rate, tumor mutation burden (TMB) value, cellular signaling pathway, differentially expressed genes (DEGs), and drug resistance in the two FPI groups were identified. Human PCa cells, LNCaP, were treated with ferroptosis inducer erastin or inhibitor ferrostatin-1. The expression of hub genes was detected by qRT-PCR and Western blot. Results: A high FPI level was significantly related to poor BCR-free survival. Also, higher TMB value was found in the FPI-high group, and FPI was shown to be associated with gene mutations. Then, genes in both groups were revealed to be enriched in different pathways. A total of 310 DEGs were identified to be involved in muscle system processes and neuroactive ligand–receptor interactions. A total of 101 genes were found to be related to BCR-free survival, and a protein–protein interaction (PPI) network was constructed. Two sub-modules were identified by MCODE, and eight hub genes were screened out, among which SYT4 had higher expression levels and poorer BCR-free survival in the FPI-high group, while the remaining hub genes had lower expression levels and poorer BCR-free survival. Drug sensitivity was revealed to be different in the two groups by study on the IC50 data of different molecules and ferroptosis regulator gene (FRG) expressions. Finally, erastin increased the expression of SYT4 in LNCaP and decreased the expression of the other four genes (ACTC1, ACTA1, ACTN2, and MYH6), while ferrostatin-1 led to the opposite results. The molecular experimental results were consistent with those of bioinformatics analysis, except TNNI1, TNNC2, and NRAP. Conclusion: The current research depicted the ferroptosis level and FRGs in PCa. Ferroptosis was related to TMB value, BCR-free survival, and drug resistance. This study will be beneficial to further research studies on ferroptosis-related molecular mechanisms.

Dataset Information

Epigenetic Regulation of Ferroptosis-Associated Genes and Its Implication in Cancer Therapy.

Publications

Epigenetic Regulation of Ferroptosis-Associated Genes and Its Implication in Cancer Therapy.

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