CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis

Huang, D.H.; Li, Qian; Sun, Xinpei; Sun, Xiwen; Tang, Yunyi; Qu, Yanan; Liu, Dawei; Yu, Tingting; Li, Guodong; Tong, Tanjun

doi:10.1038/s41418-020-00689-5

Cited by 21 publications

(18 citation statements)

References 74 publications

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“…Some studies demonstrated the indirect regulation of ferroptosis via DNA and protein methylation. For example, lymphoid-specific helicase (LSH), a DNA methylation modifier, can activate lipid metabolism-associated genes to inhibit ferroptosis by interacting with WDR76 ( Jiang et al, 2017 ), and together with another W40 protein DCAF8, they function as a crucial nexus in epigenetic regulation of ferroptosis, controlling LSH degradation by adapted oxidative damage sensing through DNA hydroxymethylation ( Huang et al, 2020 ). The silencing of the DNA methylation of the elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) leads to ferroptosis resistance, and these two enzymes are usually upregulated in mesenchymal-type gastric cancer cells ( Lee J.-Y.…”

Section: Ferroptosis and Epigeneticsmentioning

confidence: 99%

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

Liu

et al. 2021

Front. Cell Dev. Biol.

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Cell death induction has become popular as a novel cancer treatment. Ferroptosis, a newly discovered form of cell death, features regulated, iron-dependent accumulation of lipid hydroperoxides. Since this word “ferroptosis” was coined, numerous studies have examined the complex relationship between ferroptosis and cancer. Here, starting from the intrinsic hallmarks of cancer and cell death, we discuss the theoretical basis of cell death induction as a cancer treatment. We review various aspects of the relationship between ferroptosis and cancer, including the genetic basis, epigenetic modification, cancer stem cells, and the tumor microenvironment, to provide information and support for further research on ferroptosis. We also note that exosomes can be applied in ferroptosis-based therapy. These extracellular vesicles can deliver different molecules to modulate cancer cells and cell death pathways. Using exosomes to control ferroptosis occurring in targeted cells is promising for cancer therapy.

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Section: Ferroptosis and Epigeneticsmentioning

confidence: 99%

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…A recent study showed that LSH could contribute the recruitment of WDR76 to the metabolic gene promoters such as stearoyl-CoA desaturase 1(SCD1) and fatty acid desaturases 2 (FADS2) to upregulate their expressions, which could affect the intracellular levels of iron and lipid reactive oxygen species (ROS) to block ferroptosis (Jiang et al, 2017). WDR76 was also identified as a molecular inhibitor of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of LSH and as a crucial regulator in epigenetic regulation of ferroptosis (Huang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

The correlation of WDR76 expression with survival outcomes and immune infiltrates in lung adenocarcinoma

Fang

et al. 2021

PeerJ

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Background WD repeat domain 76 (WDR76) is a predicted member of the WD40-repeat-containing domain superfamily and possibly involves in various biological processes, but its function in cancers is poorly characterized. This study aimed to evaluate the role of WDR76 in the prognosis and immune infiltrates of lung adenocarcinoma (LUAD). Methods WDR76 expressions in LUAD tissues and normal tissues were primarily compared by The Cancer Genome Atlas (TCGA) database, and were validated in cohorts from Gene Expression Omnibus (GEO) database. The associations between WDR76 expression and clinicopathologic characteristics were analyzed. Kaplan–Meier and Cox regression analyses were performed to determine the impact of WDR76 expression on survival outcomes. The protein interaction network of WDR76 was built using STRING website. TIMER and GEPIA databases were used to investigate the correlation between WDR76 expression and immune infiltrates. Results WDR76 expression was elevated in LUAD (P < 0.001) and high WDR76 expression was associated with advanced N stage, M stage and pathologic stage. Expectedly, high WDR76 expression significantly correlated with poor survival outcomes and was the independent risk factor for overall survival (OS) (HR 1.468, 95% CI [1.031–2.089], P = 0.033) and disease specific survival (DSS) (HR 1.764, 95% CI [1.095–2.842], P = 0.020). DDB1 and LSH were the important proteins interacting with WDR76. WDR76 expression correlated with CD8+ T cells presence and was also positively associated with levels of inhibitory receptors. Conclusion WDR76 expression was involved in the regulation of immune infiltrates and had predictive value for prognosis in LUAD.

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“…Moreover, LSH has been uncovered to be associated with WD40repeat protein 76 (WDR76) to inhibit ferroptosis by activating lipid metabolism-associated genes, including glucose transporter 1 (GLUT1), ferroptosis-related gene stearoyl-CoA desaturase 1 (SCD1), and fatty acid desaturase 2 (FADS2) (Jiang et al, 2017). It has been reported that erastin induces LSH destabilization, and CRL4-DCAF8 synergizes with WDR76 to control the protein levels of LSH (Huang et al, 2020). E3 ligase CRL4-DCAF8 mediates polyubiquitination and proteasomal degradation of LSH, and WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4-DCAF8-LSH complex assembly (Huang et al, 2020).…”

Section: Ubiquitination In Iron Metabolismmentioning

confidence: 99%

“…It has been reported that erastin induces LSH destabilization, and CRL4-DCAF8 synergizes with WDR76 to control the protein levels of LSH (Huang et al, 2020). E3 ligase CRL4-DCAF8 mediates polyubiquitination and proteasomal degradation of LSH, and WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4-DCAF8-LSH complex assembly (Huang et al, 2020).…”

Section: Ubiquitination In Iron Metabolismmentioning

confidence: 99%

Regulation of Ferroptosis Pathway by Ubiquitination

Wang

et al. 2021

Front. Cell Dev. Biol.

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Ferroptosis is an iron-dependent form of programmed cell death, which plays crucial roles in tumorigenesis, ischemia–reperfusion injury and various human degenerative diseases. Ferroptosis is characterized by aberrant iron and lipid metabolisms. Mechanistically, excess of catalytic iron is capable of triggering lipid peroxidation followed by Fenton reaction to induce ferroptosis. The induction of ferroptosis can be inhibited by sufficient glutathione (GSH) synthesis via system Xc– transporter-mediated cystine uptake. Therefore, induction of ferroptosis by inhibition of cystine uptake or dampening of GSH synthesis has been considered as a novel strategy for cancer therapy, while reversal of ferroptotic effect is able to delay progression of diverse disorders, such as cardiopathy, steatohepatitis, and acute kidney injury. The ubiquitin (Ub)–proteasome pathway (UPP) dominates the majority of intracellular protein degradation by coupling Ub molecules to the lysine residues of protein substrate, which is subsequently recognized by the 26S proteasome for degradation. Ubiquitination is crucially involved in a variety of physiological and pathological processes. Modulation of ubiquitination system has been exhibited to be a potential strategy for cancer treatment. Currently, more and more emerged evidence has demonstrated that ubiquitous modification is involved in ferroptosis and dominates the vulnerability to ferroptosis in multiple types of cancer. In this review, we will summarize the current findings of ferroptosis surrounding the viewpoint of ubiquitination regulation. Furthermore, we also highlight the potential effect of ubiquitination modulation on the perspective of ferroptosis-targeted cancer therapy.

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CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis

Cited by 21 publications

References 74 publications

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

The correlation of WDR76 expression with survival outcomes and immune infiltrates in lung adenocarcinoma

Regulation of Ferroptosis Pathway by Ubiquitination

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