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M6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell cycle progression and HIF-1α activation

ABSTRACT: To further delineate the downstream regulatory mechanism underlying the oncogenic roles of LINK-A, we performed mass spectrometry (MS) analyses to identify proteins precipitated with LINK-A in KYSE450 and YES2 cells. In total, 43 and 14 LINK-A-interacting proteins were identified in KYSE450 and YES2 cells, respectively, and 7 of these interacting proteins were identified in both cell lines

ORGANISM(S): Homo Sapiens

SUBMITTER: Zhihua Liu

PROVIDER: PXD045414 | iProX | Fri Sep 15 00:00:00 BST 2023

REPOSITORIES: iProX

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m6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation.

Nan Yabing Y Liu Shi S Luo Qingyu Q Wu Xiaowei X Zhao Pengfei P Chang Wan W Zhang Ruixiang R Li Yin Y Liu Zhihua Z

Cell reports 20231019 10

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression, yet its role in regulating long noncoding RNAs during cancer progression remains unclear. Here, we report that the m6A demethylase fat mass and obesity-associated protein (FTO) stabilizes long intergenic noncoding RNA for kinase activation (LINK-A) to promote cell proliferation and chemoresistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A promotes the intera ...[more]

PMID: 37858471

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m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation

Project description:We identified that the m6A demethylase FTO demethylates and stabilizes a lncRNA long intergenic noncoding RNA for kinase activation (LINK-A) during ESCC chemoresistance. LINK-A directly interacts with minichromosome maintenance complex component 3 (MCM3) and increases the phosphorylation of MCM3 at Ser112 by cyclin-dependent kinase 1 (CDK1), which facilitates MCM3 incorporation into the MCM2-7 complex and subsequent chromatin loading, promoting cell cycle progression. On the other hand, LINK-A insulates the interaction between MCM3 and HIF-1α to free HIF-1α. The enhancement of HIF-1α transcriptional activity reprograms metabolic status from OXPHOS to glycolysis. Additionally, targeting LINK-A substantially sensitized ESCC patient-derived xenografts (PDXs) to first-line chemotherapy, thus indicating LINK-A is a promising target for cancer treatment.

2023-10-15 | GSE224079 | GEO

m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation

Project description:m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation

| PRJNA929528 | ENA

m6A demethylase Fto inhibited macrophage activation and glycolysis in diabetic nephropathy via m6A/Npas2/Hif-1α axis.

Project description:Macrophage infiltration and activation is a key factor in the progression of diabetic nephropathy (DN). However, aerobic glycolysis induced by m6A methylation modification plays a key role in M1-type activation of macrophages, but the specific mechanism remains unclear in DN. In this study, the expression of m6A demethylase Fto in bone marrow derived macrophages and primary kidney macrophages from db/db mice. Loss and gain-of-function analysis of Fto were performed to assess the role of Fto in DN. Transcriptome and MeRIP-seq association analysis was performed to identified the target gene was Npas2. In this study, we found that demethylase Fto exhibits low expression in type 2 DN m6A modification of Npas2 mediated by Fto regulates macrophages M1-type activation and glucose metabolism reprogramming to participate in the process of DN. Furthermore, Fto reduces the m6A modification level of Npas2 in macrophages through a Prrc2a-dependent mechanism, and decreasing its stability. This process mediates inflammation and glycolysis in M1 macrophages by regulating the Hif-1α signaling pathway. Fto may act as a suppressor of M1 macrophages inflammation and glycolysis in DN through the m6A/Npas2/Hif-1α axis. This findings providing a new basis for the prevention and treatment of DN.

| S-EPMC11744739 | biostudies-literature

Citrullination modulation stabilizes HIF-1α to promote tumour progression.

Project description:Citrullination plays an essential role in various physiological or pathological processes, however, whether citrullination is involved in regulating tumour progression and the potential therapeutic significance have not been well explored. Here, we find that peptidyl arginine deiminase 4 (PADI4) directly interacts with and citrullinates hypoxia-inducible factor 1α (HIF-1α) at R698, promoting HIF-1α stabilization. Mechanistically, PADI4-mediated HIF-1αR698 citrullination blocks von Hippel-Lindau (VHL) binding, thereby antagonizing HIF-1α ubiquitination and subsequent proteasome degradation. We also show that citrullinated HIF-1αR698, HIF-1α and PADI4 are highly expressed in hepatocellular carcinoma (HCC) tumour tissues, suggesting a potential correlation between PADI4-mediated HIF-1αR698 citrullination and cancer development. Furthermore, we identify that dihydroergotamine mesylate (DHE) acts as an antagonist of PADI4, which ultimately suppresses tumour progression. Collectively, our results reveal citrullination as a posttranslational modification related to HIF-1α stability, and suggest that targeting PADI4-mediated HIF-1α citrullination is a promising therapeutic strategy for cancers with aberrant HIF-1α expression.

| S-EPMC11372217 | biostudies-literature

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

Project description:This corrects the article DOI: 10.1038/onc.2017.8.

| S-EPMC5537603 | biostudies-other

IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer

Project description:Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma.

| S-SCDT-10_15252-EMBJ_2022110620 | biostudies-other

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

Project description:GATA binding protein 3 (GATA3) is indispensable in development of human organs. However, the role of GATA3 in cancers remains elusive. Hypoxia inducible factor (HIF)-1 plays an important role in pathogenesis of human cancers. Regulation of HIF-1α degradation is orchestrated through collaboration of its interacting proteins. In this study, we discover that GATA3 is upregulated in head and neck squamous cell carcinoma (HNSCC) and is an independent predictor for poor disease-free survival. GATA3 promotes invasive behaviours of HNSCC and melanoma cells in vitro and in immunodeficient mice. Mechanistically, GATA3 physically associates with HIF-1α under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1α, which is independent of HIF-1α prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1α complex binds to and regulates HIF-1 target genes, which is also supported by the microarray analysis. Notably, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown, suggesting a critical role of HIF-1α in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1α to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1α axis as a potential therapeutic target for cancer treatment.

| S-EPMC5537608 | biostudies-literature

NF-κB1 p50 stabilizes HIF-1α protein through suppression of ATG7-dependent autophagy.

Project description:The function and underlying mechanisms of p50 in the regulation of protein expression is much less studied because of its lacking of transactivation domain. In this study, we discovered a novel function of p50 in its stabilization of hypoxia-inducible factor 1α (HIF-1α) protein under the condition of cells exposed to arsenic exposure. In p50-deficient (p50-/-) cells, the HIF-1α protein expression was impaired upon arsenic exposure, and such defect could be rescued by reconstitutional expression of p50. Mechanistic study revealed that the inhibition of autophagy-related gene 7 (ATG7)-dependent autophagy was in charge of p50-mediated HIF-1α protein stabilization following arsenic exposure. Moreover, p50 deletion promoted nucleolin (NCL) protein translation to enhance ATG7 mRNA transcription via directly binding transcription factor Sp1 mRNA and increase its stability. We further discovered that p50-mediated miR-494 upregulation gave rise to the inhibition of p50-mediated NCL translation by interacting with its 3'-UTR. These novel findings provide a great insight into the understanding of biomedical significance of p50 protein in arsenite-associated disease development and therapy.

| S-EPMC9794792 | biostudies-literature

CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth.

Project description:Hypoxia-inducible factor 1 (HIF-1) is a major mediator of tumor physiology, and its activation is correlated with tumor progression, metastasis, and therapeutic resistance. HIF-1 is activated in a broad range of solid tumors due to intratumoral hypoxia or genetic alterations that enhance its expression or inhibit its degradation. As a result, decreasing HIF-1α expression represents an attractive strategy to sensitize hypoxic tumors to anticancer therapies. Here, we show that cyclin-dependent kinase 1 (CDK1) regulates the expression of HIF-1α, independent of its known regulators. Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1α under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1α, reducing its half-life and steady-state levels. In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1α at a previously unidentified regulatory site, Ser668. HIF-1α is stabilized under normoxic conditions during G 2/M phase via CDK1-mediated phosphorylation of Ser668. A phospho-mimetic construct of HIF-1α at Ser668 (S668E) is significantly more stable under both normoxic and hypoxic conditions, resulting in enhanced transcription of HIF-1 target genes and increased tumor cell invasion and migration. Importantly, HIF-1α (S668E) displays increased tumor angiogenesis, proliferation, and tumor growth in vivo compared with wild-type HIF-1α. Thus, we have identified a novel link between CDK1 and HIF-1α that provides a potential molecular explanation for the elevated HIF-1 activity observed in primary and metastatic tumors, independent of hypoxia, and offers a molecular rationale for the clinical translation of CDK inhibitors for use in tumors with constitutively active HIF-1.

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IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer.

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