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

Wu, Yuqing; Zhang, Siwei; Gong, Xiaoxiao; Tam, Samantha; Xiao, Desheng; Liu, Shuang; Tao, Yongguang

doi:10.1186/s12943-020-01157-x

Cited by 244 publications

(191 citation statements)

References 144 publications

(210 reference statements)

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“…Ferroptosis is a programmed cell death caused by irondependent lipid peroxidation and is different from other types of cell death, including apoptosis [14,40]. A wide variety of human diseases, including cancer, have been associated with the abnormal function of ferroptosis, and inhibition or upregulation of ferroptosis modulates the metabolic reprogramming of cancer cells [14,41]. At present, few studies have been performed on ferroptosis in KIRC, and the results also remain controversial [42].…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a Ferroptosis-Related Prognostic Signature in Kidney Renal Clear Cell Carcinoma

Sun

Jing

Xiao

et al. 2020

Preprint

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Background: Kidney renal clear cell carcinoma (KIRC) is the most common and lethal renal cell carcinoma (RCC) histological subtype. Ferroptosis is a newly discovered programmed cell death and serves an essential role in tumor occurrence and development. The purpose of this study is to analyze ferroptosis-related gene (FRG) expression profiles and to construct a multi-gene signature for predicting the prognosis of KIRC patients.Methods:RNA-sequencing data and clinicopathological data of KIRC patients were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed FRGs between KIRC and normal tissues were identified using ‘limma’ package in R. GO and KEGG enrichment analyses were conducted to elucidate the biological functions and pathways of differentially expressed FRGs. Consensus clustering was used to investigate the relationship between the expression of FRGs and clinical phenotypes. Univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis were used to screen genes related to prognosis and construct the optimal signature. Then, a nomogram was established to predict individual survival probability by combining clinical features and prognostic signature.Results: A total of 19 differentially expressed FRGs were identified. Consensus clustering identified two clusters of KIRC patients with distinguished prognostic. Functional analysis revealed that metabolism-related pathways were enriched, especially lipid metabolism. A 7-gene ferroptosis-related prognostic signature was constructed to stratify the TCGA training cohort into high- and low-risk groups where the prognosis was significantly worse in the high-risk group. The signature was identified as an independent prognostic indicator for KIRC. These findings were validated in the testing cohort, the entire cohort, and the International Cancer Genome Consortium (ICGC) cohort. We further demonstrated that the signature-based risk score was highly associated with the KIRC progression. Further stratified survival analysis showed that the high-risk group had a significantly lower overall survival (OS) rate than those in the low-risk group. Moreover, we constructed a nomogram that had a strong ability to forecast the OS of the KIRC patients.Conclusion: We constructed a ferroptosis-related prognostic signature, which might provide a reliable prognosis assessment tool for clinician to guide clinical decision-making and outcomes research.

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Section: Discussionmentioning

confidence: 99%

Construction and Validation of a Ferroptosis-Related Prognostic Signature in Kidney Renal Clear Cell Carcinoma

Sun

Jing

Xiao

et al. 2020

Preprint

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“…Moreover, sorafenib can also induce ferroptosis by triggering the expression of cathepsin B through MEK-ERK signaling phosphorylation, while inhibiting the signal transducer and activator of transcription 3 (STAT3) in human PDAC cell lines (60,62,63).…”

Section: Ferroptosis In Targeted Cancer Therapymentioning

confidence: 99%

Ferroptosis in Cancer Treatment: Another Way to Rome

Luo

et al. 2020

Front. Oncol.

118

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Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis and the development of diseases, especially cancers. Inducing ferroptosis leads to mitochondrial dysfunction and toxic lipid peroxidation in cells, which plays a pivotal role in suppressing cancer growth and progression. Here, we reviewed the existing studies about the molecular mechanisms of ferroptosis involved in different antitumor treatments, such as chemotherapy, targeted therapy, radiotherapy, and immunotherapy. We focused in particular on the distinct combinatorial therapeutic effects such as the synergistic sensitization effect and the drug-resistance reversal achieved when using ferroptosis inducers with conventional cancer therapy. Finally, we discussed the challenges and opportunities in clinical applications of ferroptosis. The application of nanotechnolgy and other novel technologies may provide a new direction in ferroptosis-driven cancer therapies.

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“…Ferroptosis is recently discovered iron-dependent cell death fueled by lipid peroxidation, which differs from necrosis and apoptosis [ 322 – 324 ]. Mitochondrial metabolism involved series of substrates consumption, is primary source of ROS via Fenton reaction that ferrous iron mixed with hydrogen peroxide (H 2 O 2 ) is equipped with strong oxidizability to oxidize many known intracellular compounds such as carboxylic acids, alcohols and esters into inorganic states with significant oxidation effect [ 325 ]. Emerging studies has revealed ROS accumulation in a variety of cells including those within malignancies.…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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

Cited by 244 publications

References 144 publications

Construction and Validation of a Ferroptosis-Related Prognostic Signature in Kidney Renal Clear Cell Carcinoma

Construction and Validation of a Ferroptosis-Related Prognostic Signature in Kidney Renal Clear Cell Carcinoma

Ferroptosis in Cancer Treatment: Another Way to Rome

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

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