N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

Xie, Rongjun; Liu, Longfei; Lu, Xianzhou; He, Chengjian; Yao, Hongyi; Li, Guoxin

doi:10.1007/s10120-023-01437-7

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…Aerobic glycolysis is the primary pathway by which tumor cells utilize glucose, known as the Warburg effect 12 , 13 . Numerous studies have indicated that tumor cells modulate the expression of glycolysis-related proteins through ubiquitin modification, thereby activating or inhibiting the glycolytic pathway 14 , 15 , 16 . For instance, the E3 ligase Fbw7 inhibits glycolysis in diffuse large B-cell lymphoma by promoting the ubiquitin-mediated degradation of LDHA 14 .…”

Section: Introductionmentioning

confidence: 99%

“…HectH9, through K63-linked ubiquitination, facilitates the transfer of HK2 to mitochondria and enhances glycolysis in prostate cancer 15 . Moreover, TRIM21, by means of ubiquitinating hnRNPA1 and thereby inducing degradation, curtails aerobic glycolysis in gastric cancer cells 16 . However, further investigation is needed to determine whether TRIM50 can modulate glycolysis in GC cells through its function as a ubiquitin ligase.…”

Section: Introductionmentioning

confidence: 99%

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TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1

Gu,

Xia,

et al. 2024

Int. J. Biol. Sci.

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Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo . Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1

Gu,

Xia,

et al. 2024

Int. J. Biol. Sci.

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“…Furthermore, m6A modification participates in the various aspects of tumor development, such as immunity, metabolism, and tumor stem cells’ self-renewal[ 18 , 19 ], emerging as an important molecular biomarker in tumor initiation and development. m6A dysregulation exerts multiple regulatory effects in GC[ 20 , 21 ]. The pathogenic mechanism of H. pylori as a significant risk factor for GC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway

An,

Hu,

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Helicobacter pylori (H. pylori ) colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying H. pylori -induced HIF-1α expression and carcinogenesis remain unclear. AIM To explore the underlying mechanism of H. pylori -induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1). METHODS The study was conducted with human GES-1 cells in vitro . Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of METTL14 and HIF-1α were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively. RESULTS H. pylori promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in H. pylori -infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect. CONCLUSION H. pylori- induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.

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N6-methyladenosine modification of linc-OIP5 confers paclitaxel resistance in breast cancer through a DDX5-dependent mechanism

Wang,

Li,

Zhang

et al. 2024

Experimental Cell Research

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N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

Cited by 3 publications

References 51 publications

TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1

TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1

N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway

N6-methyladenosine modification of linc-OIP5 confers paclitaxel resistance in breast cancer through a DDX5-dependent mechanism

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