MOLECULAR BIOTECHNOLOGY
·
2023
·
IF 2.6
Lv Chen-Guang,Cheng Yao,Zhang Lei,Wu Guo-Gang,Liang Chun-Yan,Tao Zuo,Chen Bo
BC (breast cancer) is the leading cause of cancer death in women. Exosome component 2 (EXOSC2), an RNA exosome component, is elevated in BC tissues and may relate to BC carcinogenesis. In this work, the high EXOSC2 expression was correlated with TNM (Tumor Node Metastasis) stage. Moreover, overexpression of EXOSC2 enhanced tumorigenic capacity of BC cells via facilitating cell proliferation and cell cycle progression, increasing migration and angiogenesis, as well as exacerbating xenograft formation in vivo. Whereas, EXOSC2 knockdown showed anti-cancer effects, including inhibition of cell proliferation and angiogenesis. Mechanistically, EXOSC2 activated the wnt/β-catenin pathway, which was also abolished by EXOSC2 knockdown. In addition, there were m6A methylation modification sites in the mRNA of EXOSC2. WTAP (Wilms tumor 1-associated protein) bound to EXOSC2 mRNA and increased its m6A methylation, resulting in extending the half-life of EXOSC2 mRNA. Luciferase data also confirmed that WTAP enhanced EXOSC2 mRNA stability through binding with the 3′-UTR containing m6A sites. Furthermore, WTAP silencing exhibited cancer-inhibiting effects on cell viability, cell cycle progression and tube formation, which was effectively reversed by EXOSC2 overexpression. In conclusion, our results demonstrate that EXOSC2 promotes the malignant behaviors of BC cells via activating the wnt/β-catenin pathway. In addition, EXOSC2 mediates the function of WTAP which contributes to the m6A modification of EXOSC2. Totally, this study suggested that EXOSC2 mediated the pro-tumor role of WTAP via activating the wnt/β-catenin signal.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 12
·1-16
·
IF 8.1
Hou Rui,Sun Xinrui,Cao Shiyao,Wang Yadong,Jiang Luo
The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH + CD133 + FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3’UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.
研究领域:
肿瘤学
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分子生物学
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代谢组学
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癌症生物学
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表观遗传学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Dongkai Jia,Lulu Liu,Wei Liu,Mengrou Geng,Jinjie Li,Haoqiang Guo,Ke Xu,Pinyi Liu,Ying Xin
Cuproptosis is a recently identified form of regulated cell death triggered by intracellular copper (Cu) overload. Diabetic conditions are characterized by disrupted Cu homeostasis. This study reveals a critical mechanistic link between the RNA methyltransferase WTAP and hypoxia-inducible factor-2α (HIF-2α) in promoting cardiomyocyte cuproptosis in diabetic cardiomyopathy (DCM). In both diabetic mouse hearts and high-fat/high-glucose plus Cu chloride-treated AC16 cardiomyocytes, elevated levels of WTAP and HIF-2α were observed alongside increased cuproptosis. Mechanistically, WTAP facilitates m 6 A-dependent upregulation of HIF-2α, which transcriptionally activates the divalent metal transporter 1 (DMT1). Enhanced DMT1 expression leads to intracellular Cu accumulation, subsequently inducing cuproptosis and driving DCM progression. Importantly, the clinically used agent dexmedetomidine (DEX) was found to alleviate DCM in vivo, at least in part, by suppressing DMT1 expression and thereby inhibiting cuproptosis. These findings identify the WTAP/HIF-2α/DMT1 axis as a key regulator of Cu overload and cuproptosis in DCM, highlighting its therapeutic potential.
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高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 15
·e72061
·
IF 4.3
Wei Liu,Yuqin Wang,Jiayuan Wu,Caihong He,Zhengwei Zhou
Lactate, a metabolic byproduct of glycolysis, accumulates during myocardial infarction and ischemia/reperfusion (I/R) injury, acting as both a metabolic stress marker and a signaling molecule that influences inflammation and cell fate. Lactate can induce histone lysine lactylation (Kla), a novel post‐translational modification that regulates gene transcription and immune responses. Despite this discovery, its role in I/R injury remains unclear. To investigate the effects of lactate and histone lactylation, both in vivo myocardial I/R injury and in vitro hypoxia/reoxygenation (H/R) injury models using cardiomyocytes were established. Lipid peroxidation, LDH, MDA, SOD, and iron levels were quantified using specialized fluorescent probes and commercial kits. MeRIP and RIP assays were performed to investigate WTAP, YTHDF1, and ALOX15 interactions. TEM was utilized to examine mitochondrial ultrastructure and morphology. Lactate levels were elevated in I/R rats, and reducing lactate levels effectively mitigated ferroptosis and myocardial injury. Furthermore, lactate promoted Kla of WTAP, resulting in upregulation of WTAP protein expression compared to the I/R group. Global m 6 A RNA methylation levels increased by lactate treatment. Elevated WTAP levels, or overexpression of YTHDF1, facilitated m6A modification of ALOX15 mRNA, leading to upregulation of ALOX15 expression and enhanced ferroptosis during I/R injury. Notably, overexpression of ALOX15 reversed the protective effects of WTAP knockdown. Finally, we validated the involvement of the WTAP‐YTHDF1‐ALOX15 regulatory axis in vivo. Lactate‐induced Kla of WTAP led to its upregulation, which, together with YTHDF1, facilitated the m6A modification of ALOX15 mRNA. This modification increased ALOX15 expression, triggering cardiomyocyte ferroptosis and worsening myocardial I/R injury. These findings highlight the potential of targeting lactate‐induced Kla and its downstream effectors, including WTAP, YTHDF1, and ALOX15, as therapeutic strategies. Lactate accumulation during myocardial ischemia–reperfusion injury enhances histone lactylation and WTAP expression, promoting m 6 A modification of ALOX15 mRNA through YTHDF1. This regulatory axis increases ALOX15 expression, lipid peroxidation, and ferroptosis, thereby aggravating myocardial injury. Targeting WTAP lactylation or the WTAP/YTHDF1/ALOX15 pathway may provide a potential therapeutic strategy for myocardial ischemia–reperfusion injury.
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PubMed
高影响因子
CANCER GENE THERAPY
·
2026
·
IF 6.4
Shi Ruxue,Gu Kai,Li Haichuan,Sun Qingwei,Wu Xinyu,Huang Shuhong,Hu Qingxia
Castration-resistant prostate cancer (CRPC) is one of the most prevalent cancers in men. The new generation androgen receptor (AR) inhibitor enzalutamide can improve the therapeutic effectiveness of patients with CRPC. However, these patients eventually develop acquired enzalutamide resistance (ENZR), and the mechanisms underlying resistance are not well understood. Wilms’ tumor 1-associating protein (WTAP) plays an important role in m 6 A modification and has been reported as an oncogene in various cancers. Here, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m 6 A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors. The alternative text for this image may have been generated using AI. In this manuscript, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m 6 A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors.
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PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2023
·
IF 4.5
Chen Guo,Mingyi Yu,Jinghua Liu,Zhe Jia,Hui Liu,Shaozhen Zhao
Dry eye disease (DED) is often secondary to diabetes mellitus (DM). We explored the action of Wilms tumor 1-associated protein (WTAP) in DM-DED via lncRNA NEAT1 m6A methylation. DM-DED mouse models were treated with sh-WTAP/sh-NEAT1 plasmid, followed by assessment of corneal epithelial damage/histopathological changes. HCE-2 cells were exposed to hyperosmotic conditions to establish in vitro DED models and treated with oe-NEAT1/sh-NEAT1/sh-WTAP/nigericin (an NLRP3 inflammasome inducer). Cell viability/apoptosis were evaluated by CCK-8/TUNEL. The levels of WTAP/NEAT1/inflammatory factors/NLRP3 inflammasome- and apoptosis-related markers were determined. m6A modification was examined by MeRIP-qPCR and NEAT1 stability was also detected. DM-DED mice exhibited up-regulated WTAP/NEAT1 expression and severe corneal damage, whereas WTAP/NEAT1 knockdown alleviated inflammation/corneal damage. In hyperosmolarity-induced HCE-2 cells, NEAT1 aggravated inflammation and apoptosis, while NEAT1 knockdown suppressed NLRP3 inflammasome activation and ameliorated cell injury. Hyperosmolarity-induced WTAP expression increased m6A modification and NEAT1 mRNA stability. WTAP mediated m6A methylation of NEAT1 and NLRP3 inflammasome activation in DM-DED mice. Collectively, WTAP upregulates NEAT1 expression and facilitates NLRP3 inflammasome activation by increasing m6A methylation, thereby accelerating DM-DED development. WTAP or lncRNA NEAT1 may become a therapeutic target for DM-DED, which offers a theoretical foundation for the investigation and advancement of nanocarrier-based targeted therapeutic medications for DM-DED.
研究领域:
眼科学
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分子生物学
·
糖尿病研究
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炎症
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细胞生物学
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DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2023
·Vol. 30
·期 29
·3368-3381
·
IF 4.1
Dai Xiaoyu,Chen Ke,Xie Yangyang
Background: The role of WT1-associated protein (WTAP) in mediating the N6-methyladenosine (m6A) modification of pyruvate dehydrogenase kinase 4 (PDK4) in colorectal cancer (CRC) has been previously reported. Objective: This research manages to unveil the function and mechanism
of WTAP mediating the m6A modification in CRC. Methods: Expressions of PDK4 and WTAP in CRC were assessed by bioinformatics analysis and verified by Western blot. After the transfection with short hairpin RNAs (shRNAs) for WTAP (shWTAP) and PDK4 (shPDK4) to manipulate the expressions
of PDK4 and WTAP, the viability, proliferation, migration, invasion, and levels of m6A, PDK4 and WTAP in CRC cells were determined by cell counting kit-8 (CCK-8), colony formation, transwell, Western blot, or M6A-RNA immunoprecipitation (MeRIP)-qPCR assays. M6A binding sites in PDK4 were additionally
predicted through bioinformatics analysis, and the interaction of PDK4 and WTAP was confirmed using an RNA pull-down assay. Tumor volume and weight in the constructed xenograft-tumor mouse model were recorded. Results: PDK4 expression was low, yet WTAP and m6A expressions were high in
CRC cells. WTAP bound with the m6A binding sites in PDK4. PDK4 silencing facilitated the viability, proliferation, migration and invasion, inhibited the expression of PDK4 in CRC cells, and accelerated the growth of xenografts in vivo. However, the depletion of WTAP4 exerted the opposite effects
and further offset the impact of PDK4 silencing. Conclusion: WTAP mediates the m6A modification of PDK4 to regulate the malignant behaviors of CRC cells in vitro and in vivo.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症研究
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DOI
PubMed
高影响因子
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