O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

Zhu, Guo‐Qing; Murshed, Abduh; Li, Haojie; Ma, Ji; Zhen, Ni; Ding, Miao; Zhu, Jun; Mao, Siwei; Tang, Xiaochen; Liu, Li; Sun, Fenyong; Jin, Lei; Pan, Qiuhui

doi:10.1038/s41420-021-00468-2

Cited by 65 publications

(56 citation statements)

References 36 publications

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“…A newly identified circular RNA, Circ0097009, could upregulate the expression of SLC7A11, a key ferroptosis-associated regulator, by sponging miR-1261 in multiple HCC cell lines (42). O-GlcNAcylationmediated YAP stabilization enhanced the sensitivity of HCC cells to RSL3-induced ferroptosis in vitro and in vivo (43). Recent studies have reported the direct crosstalk between ferroptosis and anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 97%

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma

Peng²,

Liang³

et al. 2021

Front. Immunol.

115

108

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Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson’s test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman’s correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.

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Section: Discussionmentioning

confidence: 97%

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma

Peng²,

Liang³

et al. 2021

Front. Immunol.

115

108

View full text Add to dashboard Cite

show abstract

“…TFRC and DMT1 mediate ferrous iron formation and transport [ 33 ]. Previous studies suggest that downregulation of TFRC expression inhibits ferroptosis [ 34 ], and overexpression of TFRC could increase iron levels to increase ferroptosis sensitivity [ 35 ]. Similar to TFRC, DMT1 is also a positive regulator of iron accumulation, leading to ferroptosis [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells

Luo

Gao

Zou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a new form of regulated cell death, which is mediated by intracellular iron. Although it is reported that bavachin has antitumour effects on several tumour cells and prompts the reactive oxygen species (ROS) generation, it is unclear whether ferroptosis can be induced by bavachin in osteosarcoma (OS) cells. In this study, we found that bavachin inhibits the viability of MG63 and HOS OS cell lines along with an increase in the ferrous iron level, ROS accumulation, malondialdehyde overexpression, and glutathione depletion. Moreover, iron chelators (deferoxamine), antioxidants (Vit E), and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) reverse bavachin-induced cell death. Bavachin also altered the mitochondrial morphology of OS cells, leading to smaller mitochondria, higher density of the mitochondrial membrane, and reduced mitochondrial cristae. Further investigation showed that bavachin upregulated the expression of transferrin receptor, divalent metal transporter-1, and P53, along with downregulating the expression of ferritin light chain, ferritin heavy chain, p-STAT3 (705), SLC7A11, and glutathione peroxidase-4 in OS cells. More importantly, STAT3 overexpression, SLC7A11 overexpression, and pretreatment with pifithrin-α (P53 inhibitor) rescued OS cell ferroptosis induced by bavachin. The results show that bavachin induces ferroptosis via the STAT3/P53/SLC7A11 axis in OS cells.

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“…To achieve the effect of antitumor, it has the effect of anti-liver cancer when used alone. 58 Unlike the sonosensitizers we use, it does not significantly increase its efficacy under ultrasound irradiation, so we added the sonosensitizer Indocyanine Green. Sonodynamic therapy is produced by the combination of sonosensitizers and ultrasound to make Hepatocellular Carcinoma cells sensitive to RSL3-induced ferroptosis and achieve better anti-liver cancer effects.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC

Chen

Shang

Wang

et al. 2022

IJN

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Background The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) has failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention. Methods In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety. Results MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. We found that they were significantly enriched in the ferroptosis-related pathway MAPK cascade and cell proliferation. Then, we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes “SLC37A2” and “ITGB7” may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma. Conclusion The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.

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O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

Cited by 65 publications

References 36 publications

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma

Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells

RNA-Seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC

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