Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

Wohlhieter, Corrin A.; Richards, Allison L.; Uddin, Fathema; Hulton, Christopher H.; Quintanal-Villalonga, Àlvaro; Martin, Axel; Stanchina, Elisa de; Bhanot, Umesh; Asher, Marina; Shah, Nisargbhai; Hayatt, Omar; Buonocore, Darren J.; Rekhtman, Natasha; Shen, Ronglai; Arbour, Kathryn C.; Donoghue, Mark T.A.; Poirier, John T.; Sen, Triparna; Rudin, Charles M.

doi:10.1016/j.celrep.2020.108444

Cited by 150 publications

(105 citation statements)

References 42 publications

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“…ALOX12 has been reported to be the core enzyme in mediating lipid peroxidation and has significant correlation with glutathione peroxidase 4 (GPX4) ( 53 ). AKR1C1 protects cancer cells from ferroptosis and is considered as the ferroptosis-protective gene ( 54 ). In addition, AKR1C1 has been confirmed high basal expression levels in CRC and promotes tumor proliferation, metastasis, and drug resistance ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

An Original Ferroptosis-Related Gene Signature Effectively Predicts the Prognosis and Clinical Status for Colorectal Cancer Patients

et al. 2021

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BackgroundColorectal cancer (CRC) is one of the most common malignant tumors in the world. Ferroptosis is a newly defined form of cell death, distinguished by different morphology, biochemistry, and genetics, and involved in CRC progression and treatment. This study aims to establish a predictive model to elucidate the relationship between ferroptosis and prognosis of CRC patients, to explore the potential value of ferroptosis in therapeutic options.MethodsThe ferroptosis-related genes were obtained from the GeneCards and FerrDb websites. The limma R package was used to screen the differential ferroptosis-related genes (DEGs) in CRC from The Cancer Genome Atlas (TCGA) dataset. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regressions were to establish the 10-gene prognostic signature. The survival and receiver operating characteristic (ROC) curves were illustrated to evaluate the predictive effect of the signature. Besides, independent prognostic factors, downstream functional enrichment, drug sensitivity, somatic mutation status, and immune feature were analyzed. Moreover, all these conclusions were verified by using multiple datasets in International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO).ResultsTen ferroptosis-related gene signature (TFAP2C, SLC39A8, NOS2, HAMP, GDF15, FDFT1, CDKN2A, ALOX12, AKR1C1, ATP6V1G2) was established to predict the prognosis of CRC patients by Lasso cox analysis, demonstrating a good performance on Receiver operating characteristic (ROC) and Kaplan–Meier (K–M) analyses. The CRC patients in the high- or low-risk group showed significantly different fractions of immune cells, such as macrophage cells and CD8+ T cells. Drug sensitivity and somatic mutation status like TP53 were also closely associated with the risk scores.ConclusionsIn this study, we identified a novel ferroptosis-related 10-gene signature, which could effectively predict the prognosis and survival time of CRC patients, and provide meaningful clinical implications for targeted therapy or immunotherapy. Targeting ferroptosis is a good therapeutic option for CRC patients. Further studies are needed to reveal the underlying mechanisms of ferroptosis in CRC.

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Section: Discussionmentioning

confidence: 99%

An Original Ferroptosis-Related Gene Signature Effectively Predicts the Prognosis and Clinical Status for Colorectal Cancer Patients

et al. 2021

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“…Recent studies have also shown the involvement of SCD1 in the regulation of ferroptosis [ 97 , 98 ]. Tesfay and colleagues correlated high expression levels of SCD1 found in different ovarian cancer isotypes with the synthesis of lipids implicated in protection from ferroptosis, as a mevalonate metabolite CoQ10.…”

Section: The Controversial Role Of Scd1-mediated Autophagy In Cancer and Future Research Perspectivesmentioning

confidence: 99%

“…In particular, the highest therapeutic efficacy was achieved when the SCD1 inhibitor A939572 and the ferroptosis inducer erastin were administered in combination rather than as a single agent [ 97 , 99 ]. Additionally, Wohlhieter et al identified SCD1 as an essential gene for survival and ferroptosis protection in STK11/KEAP1 co-mutant lung adenocarcinoma [ 98 ], a subset of tumors characterized by resistance to available therapies and early death [ 100 ].…”

Section: The Controversial Role Of Scd1-mediated Autophagy In Cancer and Future Research Perspectivesmentioning

confidence: 99%

SCD1, autophagy and cancer: implications for therapy

Ascenzi

Vitis

Maugeri‐Saccà

et al. 2021

J Exp Clin Cancer Res

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Background Autophagy is an intracellular degradation system that removes unnecessary or dysfunctional components and recycles them for other cellular functions. Over the years, a mutual regulation between lipid metabolism and autophagy has been uncovered. Methods This is a narrative review discussing the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be exploited for therapeutic purposes. Results Fatty acids, depending on the species, can have either activating or inhibitory roles on autophagy. In turn, autophagy regulates the mobilization of fat from cellular deposits, such as lipid droplets, and removes unnecessary lipids to prevent cellular lipotoxicity. This review describes the regulation of autophagy by lipid metabolism in cancer cells, focusing on the role of stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in the synthesis of monounsaturated fatty acids. SCD1 plays an important role in cancer, promoting cell proliferation and metastasis. The role of autophagy in cancer is more complex since it can act either by protecting against the onset of cancer or by promoting tumor growth. Mounting evidence indicates that autophagy and lipid metabolism are tightly interconnected. Conclusion Here, we discuss controversial findings of SCD1 as an autophagy inducer or inhibitor in cancer, highlighting how these activities may result in cancer promotion or inhibition depending upon the degree of cancer heterogeneity and plasticity.

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“…Ferroptosis plays a key role in killing tumor cells and inhibiting tumor growth (Jiang et al, 2021;Wang H. et al, 2021). Accumulating evidence indicates that ferroptosis is involved in the biological processes of LUAD (Wohlhieter et al, 2020;Li et al, 2021;Lou et al, 2021). However, the regulation of ferroptosis remains obscure, and it is far from being applied to cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of a Ferroptosis-Related Long Non-coding RNA Signature for Predicting the Outcome of Lung Adenocarcinoma

Zheng

Zhang

et al. 2021

Front. Genet.

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BackgroundFerroptosis is a recently recognized type of programmed cell death that is involved in the biological processes of various cancers. However, the mechanism of ferroptosis in lung adenocarcinoma (LUAD) remains unclear. This study aimed to determine the role of ferroptosis-associated long non-coding RNAs (lncRNAs) in LUAD and to establish a prognostic model.MethodsWe downloaded ferroptosis-related genes from the FerrDb database and RNA sequencing data and clinicopathological characteristics from The Cancer Genome Atlas. We randomly divided the data into training and validation sets. Ferroptosis-associated lncRNA signatures with the lowest Akaike information criteria were determined using COX regression analysis and the least absolute shrinkage and selection operator. The risk scores of ferroptosis-related lncRNAs were calculated, and patients with LUAD were assigned to high- and low-risk groups based on the median risk score. The prognostic value of the risk scores was evaluated using Kaplan–Meier curves, Cox regression analyses, and nomograms. We then explored relationships between ferroptosis-related lncRNAs and the immune response using gene set enrichment analysis (GSEA).ResultsTen ferroptosis-related lncRNA signatures were identified in the training group, and Kaplan–Meier and Cox regression analyses confirmed that the risk scores were independent predictors of LUAD outcome in the training and validation sets (all P < 0.05). The area under the curve confirmed that the signatures could determine the prognosis of LUAD. The predictive accuracy of the established nomogram model was verified using the concordance index and calibration curve. The GSEA showed that the 10 ferroptosis-related lncRNAs might be associated with tumor immune response.ConclusionWe established a novel signature involving 10 ferroptosis-related lncRNAs (LINC01843, MIR193BHG, AC091185.1, AC027031.2, AL021707.2, AL031667.3, AL606834.1, AC026355.1, AC124045.1, and AC025048.4) that can accurately predict the outcome of LUAD and are associated with the immune response. This will provide new insights into the development of new therapies for LUAD.

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Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

Cited by 150 publications

References 42 publications

An Original Ferroptosis-Related Gene Signature Effectively Predicts the Prognosis and Clinical Status for Colorectal Cancer Patients

An Original Ferroptosis-Related Gene Signature Effectively Predicts the Prognosis and Clinical Status for Colorectal Cancer Patients

SCD1, autophagy and cancer: implications for therapy

Identification and Validation of a Ferroptosis-Related Long Non-coding RNA Signature for Predicting the Outcome of Lung Adenocarcinoma

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