npj Precision Oncology
·
2025
·Vol. 9
·期 1
·1-13
·
IF 8
Wang Zexuan,Guo Yaoyu,Hu Kefei,He Tingjiang,Qin Tong,Zhang Ludan,Xu Fang,Xu Yuanzhi,Cheng Mingjiao,Zhang Jintao,Zhao Qianwei
Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly characterized. In this study, we demonstrated that PGAM2 functioned as a tumor suppressor in HCC progression, and knockdown of PGAM2 promoted proliferation of HCC cells and tumor growth both in vitro and in vivo. Moreover, we identified lysine 100 (K100) in PGAM2 as the predominant deacetylation site of sirtuin-2 (SIRT2), and that deacetylation of K100 destabilized PGAM2 by promoting its ubiquitination and degradation. Importantly, we discovered that PGAM2 suppressed aerobic glycolysis through an enzymatic activity-independent mechanism in HCC cells. Mechanistic investigations revealed that PGAM2 knockdown upregulated lactate dehydrogenase A (LDHA) expression via activation of the signal transducer and activator of transcription 3 (STAT3). Furthermore, we found that knockdown of PGAM2 sensitized HCC cells to sorafenib treatment. In conclusion, these findings elucidate the tumor-suppressive role of PGAM2 in HCC progression and its post-translational regulation through SIRT2-mediated deacetylation, which provide novel biomarkers and therapeutic targets for HCC treatment.
研究领域:
肿瘤学
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分子生物学
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代谢研究
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PubMed
高影响因子
Neural Regeneration Research
·
2022
·
IF 6.058
Wei Wang,Qiu-Yuan Gong,Lin Cai,Yao Jing,Dian-Xu Yang,Fang Yuan,Hao Chen,Heng-Li Tian
Sirtuin 2 (SIRT2) inhibition or Sirt2 knockout in animal models protects against the development of neurodegenerative diseases and cerebral ischemia. However, the role of SIRT2 in traumatic brain injury (TBI) remains unclear. In this study, we found that knockout of Sirt2 in a mouse model of TBI reduced brain edema, attenuated disruption of the blood-brain barrier, decreased expression of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, reduced the activity of the effector caspase-1, reduced neuroinflammation and neuronal pyroptosis, and improved neurological function. Knockout of Sirt2 in a mechanical stretch injury cell model in vitro also decreased expression of the NLRP3 inflammasome and pyroptosis. Our findings suggest that knockout of Sirt2 is neuroprotective against TBI; therefore, Sirt2 could be a novel target for TBI treatment.
研究领域:
神经科学
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分子生物学
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神经病学
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炎症
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Hailiang Li,Zheng Ma,Wanfu Yang,Yifan Zhang,Jinping Sun,Haifeng Jiang,Faxuan Wang,Li Hou,Hechun Xia
Introduction Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Standard therapies are followed by poor patient’s survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Metformin has been reported to have anti-cancer effects. However, the precise mechanism underlying these effects remains elusive. A better understanding of its underlying mechanism will inform future experimental designs exploring metformin as a potential adjuvant therapy for GBM. This research aimed to elucidate the potential molecular mechanism of metformin in GBM by integrating proteomics and transcriptomics. Methods The study examined the effects of metformin on GBM cell lines using various methods. The U87, U251 and HA1800 were cultured and modified through PER2 knockdown and overexpression. Cell viability was assessed using the CCK8 assay, and G6PDH activity and intracellular NADPH + levels were measured with specific kits. ROS levels, mitochondrial membrane potential, cell cycle distribution and apoptosis were analyzed by flow cytometry. RNA was extracted for transcriptomic analysis through RNA sequencing, while proteomic analysis was performed on total protein from treated cells. WB detected specific proteins, and RT-qPCR quantified gene expression. In vivo experiments, GBM xenograft on nude mice treated with metformin combining radiotherapy was evaluated and received IHC and TUNEL staining for protein expression and apoptosis assessment. Statistical analyses were conducted using Prism software to identify significant group differences. Results We found that differential expressional genes and proteins relating to circadian rhythm were enriched in proteomic or transcriptomic. The expression of PER2, the key circadian gene, was up-regulated in GBM cell lines when treated with metformin. Furthermore, the expression of silent information regulator 2(SIRT2) was down-regulated, while the expression of the G6PD protein just slightly increased in GBM cell lines. Meanwhile, NADPH+ production and G6PDH enzyme activity significantly decreased. Further study validated that metformin inhibited the cell growth of GBM cell lines through up-regulating PER2 and inhibited SIRT2/G6PD signaling pathway, enhancing radiotherapy(RT) sensitivity. We also found that the inhibition of SIRT2 caused by metformin is mediated by PER2. Discussion We found the pivotal role of metformin as an effective circadian rhythm regulator. Targeting circadian clock gene to modify and rescue the dysfunctional circadian clock of GBM cells at molecular level might be an innovative way to administer cancer chronotherapy and maintain metabolic homeostasis in real world practice.
研究领域:
肿瘤学
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分子生物学
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药理学
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PubMed
高影响因子
FASEB JOURNAL
·
2024
·Vol. 38
·期 13
·e23756
·
IF 4.4
Lishen Shan,Li Chen,Wenxin Shen,Qianlan Zhou,Si Liu,Lina Han,Qinzhen Zhang,Bing Dai,Yuhong Zhao
Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as “airway remodeling”, are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-β1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-β1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-β1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-β1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.
研究领域:
呼吸病学
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免疫学
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分子生物学
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细胞生物学
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Jian Zhang,Xinlin Li,Wenqing Cui,Dingchun Lu,Yanyan Zhang,Jiajia Liao,Linlin Guo,Chunen Jiao,Ling Tao,Yini Xu,Xiangchun Shen
Accumulating evidence strongly support the key role of NLRP3-mediated pyroptosis in the pathogenesis and progression of vascular endothelial dysfunction associated with diabetes mellitus. Various studies have demonstrated that the activation or upregulation of Silent Information Regulation 2 homolog 2 (SIRT2) exerts inhibitory effect on the expression of NLRP3. Although 1,8-cineole has been found to protect against endothelial dysfunction and cardiovascular diseases, its role and mechanism in diabetic angiopathy remain unknown. Therefore, the aim of this study was to investigate the ameliorative effect of 1,8-cineole through SIRT2 on pyroptosis associated with diabetic angiopathy in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanism. The findings revealed that 1,8-cineole exhibited a protective effect against vascular injury and ameliorated pathological alterations in the thoracic aorta of diabetic mice. Moreover, it effectively mitigated pyroptosis induced by palmitic acid-high glucose (PA-HG) in HUVECs. Treatment with 1,8-cineole effectively restored the reduced levels of SIRT2 and suppressed the elevated expression of pyroptosis-associated proteins. Additionally, our findings demonstrated the occurrence of NLRP3 deacetylation and the physical interaction between NLRP3 and SIRT2. The SIRT2 inhibitor AGK2 and siRNA-SIRT2 effectively attenuated the effect of 1,8-cineole on NLRP3 deacetylation in HUVECs and compromised its inhibitory effect against pyroptosis in HUVECs. However, overexpression of SIRT2 inhibited PA-HG-induced pyroptosis in HUVECs. 1,8-Cineole inhibited the deacetylation of NLRP3 by regulating SIRT2, thereby reducing pyroptosis in HUVECs. In conclusion, our findings suggest that PA-HG-induced pyroptosis in HUVECs plays a crucial role in the development of diabetic angiopathy, which can be mitigated by 1,8-cineole.
研究领域:
药理学
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糖尿病
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血管生物学
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炎症
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分子生物学
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PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2025
·
IF 15.4
Chen Zixiang,Niu Kaifeng,Li Mengge,Deng Yuchun,Zhang Ji,Wei Di,Wang Jiaqi,Zhao Yongliang
Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.
研究领域:
肿瘤生物学
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细胞代谢
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表观遗传学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Jing-hang Li,Xian-Feng Yu,Shu-Ming Shi,Tian Lan,dan Liu,Jia-hui Leng,Li-Ying Liu,Yu-Yan He,Guan-Lin Jia,Hong-jie Xu,Il-keun Kong,Ming-Jun Zhang,Yong-Xun Jin
Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder that severely impacts female fertility. The natural dihydrochalcone trilobatin (TLB) has shown potential in managing metabolic diseases; however, its therapeutic effect on PCOS and the underlying mechanisms remain unexplored. Purpose To investigate the therapeutic potential of TLB for PCOS and to elucidate the mechanistic basis, focusing on glycolytic metabolism and mitochondrial function in granulosa cells (GCs). Methods A dehydroepiandrosterone (DHEA) -induced PCOS rat model was established and treated with two different doses of TLB or metformin.Therapeutic effects were assessed based on estrous cyclicity, ovarian morphology, serum hormone levels, and the HOMA-IR index. Key targets were identified through integrated metabolomics and bioinformatics analyses. The mechanism was further validated in vitro using dihydrotestosterone (DHT)-induced primary rat GCs, combined with molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, co-immunoprecipitation (CO-IP), and Seahorse metabolic analysis. Results TLB administration alleviated estrous cycle disruption, improved ovarian morphology, and normalized serum testosterone, luteinizing hormone, and HOMA-IR index in PCOS rats. Metabolomics and bioinformatics analyses identified SIRT2 as a primary target of TLB. Mechanistically, TLB targets SIRT2, promoting the deacetylation of pyruvate kinase M2 (PKM2) at the K305 site. This deacetylation enhanced PKM2 tetramerization and enzymatic activity, thereby ameliorating the glycolytic imbalance in GCs, as evidenced by reduced pyruvate accumulation and restored lactate production. Furthermore, TLB, via the SIRT2/PKM2 axis, improved mitochondrial function, supported by the recovery of ATP production, mitochondrial membrane potential, and mitochondrial permeability transition pore integrity, ultimately suppressing GC apoptosis. Conclusion Our findings demonstrate that TLB alleviates ovarian PCOS phenotypes by targeting SIRT2 to promote PKM2 deacetylation at K305, which effectively corrects glycolytic flux and restores mitochondrial function in GCs.
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高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2026
·
IF 3.4
Zizheng Lu,Minxiao Lin
In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. In vitro , SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for in vivo validation. Re -expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The in vivo validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.
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高影响因子
BIOLOGICAL RESEARCH
·
2023
·Vol. 56
·期 1
·1-14
·
IF 6.7
Dai Bing,Liu Si,Shen Wenxin,Chen Li,Zhou Qianlan,Han Lina,Zhang Qinzhen,Shan Lishen
Background Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and degradation. However, the role of SYVN1 in the pathogenesis of asthma is unclear. Results In the present study, an ovalbumin (OVA)-induced murine model was used to evaluate the effect of SYVN1 on asthma. An increase in SYVN1 expression was observed in the lungs of mice after OVA induction. Overexpression of SYVN1 attenuated airway inflammation, goblet cell hyperplasia and collagen deposition induced by OVA. The increased ER stress-related proteins and altered epithelial-mesenchymal transition (EMT) markers were also inhibited by SYVN1 in vivo. Next, TGF-β1-induced bronchial epithelial cells (BEAS-2B) were used to induce EMT process in vitro. Results showed that TGF-β1 stimulation downregulated the expression of SYVN1, and SYVN1 overexpression prevented ER stress response and EMT process in TGF-β1-induced cells. In addition, we identified that SYVN1 bound to SIRT2 and promoted its ubiquitination and degradation. SIRT2 overexpression abrogated the protection of SYVN1 on ER stress and EMT in vitro. Conclusions These data suggest that SYVN1 suppresses ER stress through the ubiquitination and degradation of SIRT2 to block EMT process, thereby protecting against airway remodeling in asthma.
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高影响因子
ACTA PHARMACOLOGICA SINICA
·
2020
·Vol. 42
·期 6
·987-997
·
IF 5.064
Liu Qiu-yan,Zhuang Yu,Song Xian-rui,Niu Qun,Sun Qiu-shuang,Li Xiao-nan,Li Ning,Liu Bao-lin,Huang Fang,Qiu Zhi-xia
Metabolic reprogramming is associated with NLRP3 inflammasome activation in activated macrophages, contributing to inflammatory responses. Tanshinone IIA (Tan-IIA) is a major constituent from Salvia miltiorrhiza Bunge, which exhibits anti-inflammatory activity. In this study, we investigated the effects of Tan-IIA on inflammation in macrophages in focus on its regulation of metabolism and redox state. In lipopolysaccharides (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs), Tan-IIA (10 μM) significantly decreased succinate-boosted IL-1β and IL-6 production, accompanied by upregulation of IL-1RA and IL-10 release via inhibiting succinate dehydrogenase (SDH). Tan-IIA concentration dependently inhibited SDH activity with an estimated IC 50 of 4.47 μM in LPS-activated BMDMs. Tan-IIA decreased succinate accumulation, suppressed mitochondrial reactive oxygen species production, thus preventing hypoxia-inducible factor-1α (HIF-1α) induction. Consequently, Tan-IIA reduced glycolysis and protected the activity of Sirtuin2 (Sirt2), an NAD + -dependent protein deacetylase, by raising the ratio of NAD + /NADH in activated macrophages. The acetylation of α-tubulin was required for the assembly of NLRP3 inflammasome; Tan-IIA increased the binding of Sirt2 to α-tubulin, and thus reduced the acetylation of α-tubulin, thus impairing this process. Sirt2 knockdown or application of Sirt2 inhibitor AGK-2 (10 μM) neutralized the effects of Tan-IIA, suggesting that Tan-IIA inactivated NLRP3 inflammasome in a manner dependent on Sirt2 regulation. The anti-inflammatory effects of Tan-IIA were observed in mice subjected to LPS challenge: pre-administration of Tan-IIA (20 mg/kg, ip) significantly attenuated LPS-induced acute inflammatory responses, characterized by elevated IL-1β but reduced IL-10 levels in serum. The peritoneal macrophages isolated from the mice displayed similar metabolic regulation. In conclusion, Tan-IIA reduces HIF-1α induction via SDH inactivation, and preserves Sirt2 activity via downregulation of glycolysis, contributing to suppression of NLRP3 inflammasome activation. This study provides a new insight into the anti-inflammatory action of Tan-IIA from the respect of metabolic and redox regulation.
研究领域:
免疫学
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药理学
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细胞代谢
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炎症
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氧化还原生物学
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DOI
PubMed
高影响因子
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