Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2‐dependent silencing of SLC7A11

Fan, Zhuoyang; Yang, Guowei; Zhang, Wei; Liu, Qian; Liu, Guangqin; Li, Pingping; Xu, Ligang; Wang, Jianhua; Zhang, Yan; Han, Hong; Liu, Rong; Shu, Minfeng

doi:10.1111/jcmm.16957

Cited by 103 publications

(61 citation statements)

References 64 publications

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“…As reported earlier, hypoxia can induce resistance to ferroptosis in pancreatic cancer cells [ 41 ]. Ferroptosis of liver cancer cells can be impeded by hypoxia [ 42 ]. Our results unraveled that hypoxia for 0-2 h had no predominant impact on CC cell viability, Fe 2+ , MDA, and GSH levels.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

Xiong

Nie

et al. 2022

Stem Cells International

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Objective. Cervical cancer (CC) is a prevalent cancer in women. Hypoxia plays a critical role in CC cell ferroptosis resistance. This study explored the mechanism of hypoxia in CC cell ferroptosis resistance by regulating HIF1α/KDM4A/H3K9me3. Methods. Cultured SiHa and Hela cells were exposed to CoCl2 and treated with Erastin. Cell viability was detected by MTT assay, and concentrations of iron ion, MDA and GSH were determined using corresponding kits. Expressions of KDM4A, HIF1α, TfR1, DMT1, and H3k9me3 were detected by RT-qPCR, Western blot, and ChIP assay. The correlation of KDM4A and HIF1α was analyzed on Oncomine, UALCAN, and Starbase. CC cells were co-transfected with shKDM4A or/and pcDNA3.1-HIF1α. Iron uptake and release were assessed using the isotopic tracer method. The binding relationship between HIF1α and HRE sequence was verified by dual-luciferase assay. Results. Cell viability and GSH were decreased while iron concentration, MDA, KDM4A, and HIF1α levels were increased in hypoxia conditions. The 2-h hypoxia induced ferroptosis resistance. KDM4A and HIF1α were highly-expressed in CC tissues and positively correlated with each other. KDM4A knockdown attenuated cell resistance to Erastin, increased H3K9me3 level in the HIF1α promoter region, and downregulated HIF1α transcription and translation. H3K9me3 level was increased in the HIF1α promoter after hypoxia. HIF1α overexpression abrogated the function of KDM4A knockdown on ferroptosis in hypoxia conditions. Iron uptake/release and TfR1/DMT1 levels were increased after hypoxia. Hypoxia activated HRE sequence in TfR1 and DMT1 promoters. Conclusion. Hypoxia upregulated KDM4A, enhanced HIF1α transcription, and activated HRE sequence in TfR1 and DMT1 promoters via H3K9me3, thus inducing ferroptosis resistance in CC cells.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

Xiong

Nie

et al. 2022

Stem Cells International

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“…Mechanistically, METTL14 enhances the engagement of pri-miR126 by DGCR8 and promotes the subsequent processing into miRNA126, which was recognized as a metastasis suppressor. What's more, the researchers verified the suppressive role of miR126 in Suppresses migration and invasion [111] Tumor suppressor miR-126 Suppresses metastasis [92] Tumor suppressor SLC7A11 HIF-1α YTHDF2 Suppresses hypoxia blocked-ferroptosis [112] Tumor suppressor USP48 SIRT6…”

Section: Liver Cancermentioning

confidence: 93%

“…Beyond inhibiting metastasis, METTL14 serves as a tumor suppressor involved in various biological processes. METTL14 facilitates hypoxia-blocked ferroptosis of HCC cells by catalyzing m6A modification at the mRNA 5’UTR of solute carrier family 7 member 11 (SLC7A11), then promotes YTHDF2-dependent degradation of SCL7A11 transcripts [ 112 ]. METTL14-triggered m6A methylation also inhibits the degradation of ubiquitin specific peptidase 48 (USP48) mRNA, which can deubiquitylate and stabilize sirtuin 6 (SIRT6) to suppresses glycolysis and HCC tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

et al. 2022

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Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.

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“…The m6A readers in the YTHDF protein family all play a role in promoting liver cancer progression, except for YTHDF2 [ 131 , 224 , 228 ]. YTHDF1 promotes the progression of liver cancer by regulating FZD5 [ 229 ], ATG2A/14 [ 126 ], and PI3K/AKT/mTOR signaling activity [ 230 ] and the EMT [ 231 ].…”

Section: M6a and Cancersmentioning

confidence: 99%

“…KIAA1429 regulates circular RNA DLC1 to promote cancer through m6A mediation [223]. METTL14 plays a tumor-suppressing effect in liver cancer and is the only m6A modifier that suppresses liver cancer tumorigenesis [46,[224][225][226][227]. The m6A demethylase FTO and ALKBH5 play roles in promoting liver cancer progression.…”

Section: Liver Cancermentioning

confidence: 99%

Role of m6A writers, erasers and readers in cancer

et al. 2022

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The N(6)-methyladenosine (m6A) modification is the most pervasive modification of human RNAs. In recent years, an increasing number of studies have suggested that m6A likely plays important roles in cancers. Many studies have demonstrated that m6A is involved in the biological functions of cancer cells, such as proliferation, invasion, metastasis, and drug resistance. In addition, m6A is closely related to the prognosis of cancer patients. In this review, we highlight recent advances in understanding the function of m6A in various cancers. We emphasize the importance of m6A to cancer progression and look forward to describe future research directions.

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Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2‐dependent silencing of SLC7A11

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 103 publications

References 64 publications

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

Role of m6A writers, erasers and readers in cancer

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