BIOLOGICAL PROCEDURES ONLINE
·
2024
·Vol. 26
·期 1
·1-18
·
IF 3.7
Meng Xiangchao,Chen Hongye,Tan Zhihui,Yan Weitao,Liu Yinfeng,Lv Ji,Han Meng
Abstract Breast cancer is the most common female malignancy worldwide. Ubiquitin-specific peptidase 53 (USP53) has been shown to exert cancer-suppressing functions in several solid tumors, but its role and the underlying mechanism in breast cancer has not been clearly elucidated. Therefore, we have carried out a series of detailed studies on this matter at the levels of bioinformatics, clinical tissue, cell function and animal model. We found that USP53 expression was downregulated in breast cancer specimens and was negatively correlated with the clinical stages. Gain- and loss-of-function experiments demonstrated USP53 inhibited proliferation, clonogenesis, cell cycle and xenograft growth, as well as induced apoptosis and mitochondrial damage of breast cancer cells. Co-immunoprecipitation data suggested that USP53 interacted with zinc finger MYND-type containing 11 (ZMYND11), and catalyzed its deubiquitination and stabilization. The 33–50 amino acid Cys-box domain was key for USP53 enzyme activity, but not essential for its binding with ZMYND11. The rescue experiments revealed that the anti-tumor role of USP53 in breast cancer cells was at least partially mediated by ZMYND11. Both USP53 and ZMYND11 were prognostic protective factors for breast cancer. USP53-ZMYND11 axis may be a good potential biomarker or therapeutic target for breast cancer, which can provide novel insights into the diagnosis, treatment and prognosis.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 5
·2817
·
IF 4.9
Gengchen Xie,Bo Lei,Zhijie Yin,Fei Xu,Xinghua Liu
Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms ofMTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from theMTA2gene (circMTA2) as a crucial regulator in GC progression. CircMTA2was highly expressed in GC tissues and cell lines, and circMTA2promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrainMTA2ubiquitination and stabilizeMTA2protein expression, thereby facilitating tumor progression. Moreover, circMTA2was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2suppressesMTA2degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies.Keywords:CircRNAs;MTA2;gastric cancer;UCHL3;ubiquitination
研究领域:
分子生物学
·
肿瘤学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-11
·
IF 9.6
Chu Xiufeng,Zhang Ting,Bukhari Ihtisham,Hu Mei,Xu Jixuan,Xing Yamin,Liang Xinfeng,Zhang Zisen,Zheng Pengyuan
Gasdermin D (GSDMD) is a critical pyroptosis mediator, consisting of one N-terminal pore-forming domain and one C-terminal auto-inhibitory domain. The free N-terminal domain (GD-NT), which is released through caspase-1/11 cleavage, exhibits distinct features from the full-length GSDMD (GD-FL), including oligomerization, membrane translocation, and pore-formation. However, the underlying mechanisms are not well elucidated. Here, we found that GD-NT, but not GD-FL, was massively ubiquitinated in cells. The K63-linked polyubiquitination of GD-NT at Lys236/237 (human/mouse), catalyzed by TRAF1, directly prompted its membrane translocation and pore-formation during pyroptosis. Inhibition of GD-NT ubiquitination via site-directed mutations or the UBA1 inhibitor PYR-41 suppressed cell death in several pyroptosis cell models. Additionally, applying PYR-41 in septic mice efficiently suppressed the release of IL-18 and TNFα. Thus, GD-NT ubiquitination is a key regulatory mechanism controlling its membrane localization and activation, which may provide a novel target for modulating immune activity in pyroptosis-related diseases.
研究领域:
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2024
·
IF 7.5
Swati Keshri,Mariella Vicinanza,Michael Takla,David C. Rubinsztein
The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with ubiquitin-specific protease 7 (USP7) emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
研究领域:
细胞生物学
·
分子生物学
·
医学
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-12
·
IF 3.9
Wu Zhiwei,Zhang Fan,Yang Kai,He Wenfei
Breast cancer is the leading cause of cancer-related death in women worldwide, and its developmental mechanisms involve complex factors. Recent studies have shown that ferroptosis is closely related to the occurrence and progression of breast cancer. However, the role of circular RNAs (circRNAs) in regulating ferroptosis in breast cancer remains unclear. In this study, we investigated the regulatory role of circSCD1 (hsa_circ_0019512) in breast cancer. We examined the expression of circSCD1 in breast cancer cell lines and explored its impact on cell viability and colony formation. We also evaluated the involvement of circSCD1 in ferroptosis by measuring the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and intracellular iron. In vivo xenograft experiments were performed to confirm the role of circSCD1 in promoting tumor growth and inhibiting ferroptosis.Furthermore, we investigated the mechanism by which circSCD1 regulates SCD1 protein stability through ubiquitination and identified the interaction between circSCD1 and the deubiquitinase OTUB1. Our results showed that circSCD1 was upregulated in breast cancer cell lines and promoted cell viability and colony formation. Knockdown of circSCD1 increased MDA and ROS levels, decreased GSH levels, and enhanced ferroptosis in breast cancer cells. In vivo, circSCD1 knockdown significantly reduced tumor size and weight, while its overexpression enhanced tumor growth. Mechanistically, circSCD1 interacted with OTUB1 to inhibit the ubiquitination and degradation of SCD1 protein, thereby stabilizing its expression. Rescue experiments demonstrated that SCD1 overexpression partially reversed the effects of circSCD1 knockdown on cell proliferation and ferroptosis. Our findings suggest that circSCD1 plays a crucial role in promoting breast cancer cell growth and inhibiting ferroptosis by regulating SCD1 protein stability. Targeting the circSCD1/OTUB1/SCD1 axis may provide a potential therapeutic strategy for breast cancer treatment.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RENAL FAILURE
·
2025
·
IF 3
Ningjun Shao,Kedan Cai,Yue Hong,Lingping Wu,Qun Luo
Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates many critical genes associated with iron storage and transportation, the activity of which is influenced by E3 ligase-mediated ubiquitination. We wondered whether there is a deubiquitinase that mediates the deubiquitination of Nrf2 to stabilize Nrf2 expression and further prevent diabetic kidney disease (DKD). High glucose (HG) was applied to induce an in vitro model of DKD. The effects of HG on HK-2 cell viability, apoptosis, Fe2+ level, Nrf2, and ubiquitin-specific protease 9X (USP9X) were assessed by cell counting kit-8 (CCK-8) assay, flow cytometry, iron assay, and Western blot. The direct interaction between Nrf2 and USP9X was analyzed using co-immunoprecipitation and ubiquitination assay. After transfection and ferrostatin-1 (Fer-1) intervention, Nrf2 and USP9X levels, cell viability, apoptosis, and Fe2+ level were tested again. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) contents, and ferroptosis-related markers were assessed by ROS assay kit, ELISA, and Western blot. HG reduced cell viability and levels of USP9X and Nrf2, while elevating apoptosis and Fe2+ level. An interaction between USP9X and Nrf2 has been verified and USP9X deubiquitinated Nrf2. Nrf2 up-regulation augmented the viability, GSH content, and ferroptosis-related protein expressions, while suppressing the apoptosis, Fe2+ level, MDA, and ROS content in HG-mediated HK-2 cells, which was reversed by USP9X silencing. Fer-1 offset the combined modulation of Nrf2 and siUSP9X on HG-induced HK-2 cells. USP9X mediates Nrf2 deubiquitinase to hamper the ferroptosis in DKD in vitro.
研究领域:
分子生物学
·
肾脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2025
·
IF 7.3
Wei Xiaosong,Wang Beibei,Yang Yang,Fang Zhiwei,Yi Chengzhi,Zhang Liuhui,Fan Xin,Tang Dongdong,Zhang Lirong,Yang Xiaoming,Song Dongkui
Zinc finger protein 24 (ZNF24) is a conserved multifunctional transcription factor associated with tumorigenesis, but its function in bladder carcinogenesis remains unclear. Herein, the expression of ZNF24 was decreased in bladder cancer (BC) cells and tissues, and patients with higher expression of ZNF24 had a better prognosis. Doxycycline-induced overexpression and knockdown of ZNF24 identified its anti-proliferative and anti-metastasis role in BC in vitro and in vivo. The potential genes for the anti-cancer role of ZNF24, involving transcriptional regulation of several factors, such as dual-specificity phosphatase 1 and squalene epoxidase. E2 conjugating enzyme UBC9 and small ubiquitin-like modifier (SUMO) 1 were found to interact with ZNF24, suggesting that ZNF24 may be SUMOylated. Consistent with the expression, ZNF24 SUMOylation levels were decreased in BC cells and tissues. Pan-SUMOylation inhibition promoted protein degradation of ZNF24. UBC9 SUMOylated ZNF24 at Lys-27 (K27) site with SUMO1 modification and the K27 mutation of ZNF24 greatly damaged the protein stability of ZNF24. Cullin 3 (CUL3), a E3 ubiquitin ligase, was responsible for the degradation of ZNF24. ZNF24 SUMOylation prevented CUL3-mediated protein degradation of ZNF24. Overall, the crosstalk between the SUMOylation and ubiquitination of ZNF24 may be a novel regulatory mechanism to block tumorigenesis and development of BC.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2025
·
IF 3.5
Zilin Li,Yan Wang,Jiahui Hu,Jingyang Du,Huizong Nie,Yiling Xi,Yue Huang,Kexin Wang,Kaixuan Zhang,Qiuran Xu,Liyan Cheng,Dongsheng Huang,Linglan Tu
Background Hepatocellular carcinoma (HCC) is a significant malignant tumor that is typically diagnosed late and has a poor prognosis. USP28 (Ubiquitin-specific protease 28), a deubiquitinating enzyme within the ubiquitin-specific proteases (USPs) family, plays a pivotal role in various biological processes, especially in cancer progression. However, its functions and molecular mechanisms in HCC are still unknown. Methods We first analyzed the expression level of USP28 in HCC tissues relative to normal tissues using TCGA database. This was further validated by qRT-PCR and Western Blot. To investigate the function of USP28 in HCC, CCK-8 assay, clone formation assay and Transwell assay were performed in control and USP28 knockdown or overexpressed HCC cells. To explore potential downstream targets of USP28, we used IP-MS analysis. The interaction between USP28 and KRT1 was confirmed by immunoprecipitation and immunofluorescence staining. Finally, we evaluated the in vivo effects of USP28 on HCC growth and metastasis using a ectopic tumor-bearing mouse model. Results The expression of USP28 in HCC tissues was significantly higher than that in normal tissues, and its high expression was associated with poor prognosis. Functional experiments showed that down-regulation of USP28 expression effectively inhibited the proliferation, migration and invasion of HCC cells, while overexpression of USP28 produced the opposite effect. Mechanistic investigations demonstrated that USP28 interacted with KRT1 and exerted deubiquitination on KRT1, thereby maintaining the stability of KRT1. Further studies revealed that USP28 knockdown resulted in decreased IFITM3 expression, which inhibited HCC cell proliferation. In addition, USP28 knockdown combined with sorafenib inhibited tumor growth and metastasis in tumor xenograft mice model. Conclusions Our study confirmed the carcinogenic effects of USP28 by stabilizing KRT1 expression and promoting IFITM3. USP28 small molecule inhibitors can inhibit the proliferation of hepatocellular carcinoma cells and enhance the sensitivity of hepatocellular carcinoma cell lines to sorafenib. This provides a theoretical basis for USP28 to be a new clinical method to alleviate sorafenib resistance.
研究领域:
肿瘤学
·
分子生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-14
·
IF 15.7
Tong Li,Wang Jie,Ma Yunjin,Wang Chunying,Fu Yue,Li Qi,Gao Chengjiang,Song Hui,Qin Ying,Zhao Chunyuan,Zhao Wei
Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense aren’t well studied. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous iron suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.
研究领域:
微生物学
·
免疫学
·
生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Tian-Jiao Li,Kai-Zhou Jin,Hong-Yu Zhou,Zhen-Yu Liao,Hui-Ru Zhang,Sai-Meng Shi,Meng-Xiong Lin,Shou-Jie Chai,Qing-Lin Fei,Long-Yun Ye,Xian-Jun Yu,Wei-Ding Wu
Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.
研究领域:
肿瘤学
·
分子生物学
·
癌症生物学
·
转化医学
✓ 已验证
DOI
PubMed
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-15
·
IF 5.2
Gong Ting-Ting,Liu Fang-Hua,Xiao Qian,Li Yi-Zi,Wei Yi-Fan,Xu He-Li,Cao Fan,Sun Ming-Li,Jiang Feng-Li,Tao Tao,Ma Qi-Peng,Qin Xue,Song Yang,Gao Song,Wu Lang,Zhao Yu-Hong,Huang Dong-Hui,Wu Qi-Jun
Platinum-based chemotherapy remains one of the major choices for treatment of ovarian cancer (OC). However, primary or acquired drug resistance severely impairs their efficiency, thereby causing chemotherapy failure and poor prognosis. SH3 domain containing ring finger 2 (SH3RF2) has been linked to the development of cancer. Here we find higher levels of SH3RF2 in the tumor tissues from cisplatin-resistant OC patients when compared to those from cisplatin-sensitive patients. Similarly, cisplatin-resistant OC cells also express higher levels of SH3RF2 than normal OC cells. Through in vitro and in vivo loss-of-function experiments, SH3RF2 is identified as a driver of cisplatin resistance, as evidenced by increases in cisplatin-induced cell apoptosis and DNA damage and decreases in cell proliferation induced by SH3RF2 depletion. Mechanistically, SH3RF2 can directly bind to the RNA-binding protein mRNA processing factor (RBPMS). RBPMS has been reported as an inhibitor of cisplatin resistance in OC. As a E3 ligase, SH3RF2 promotes the K48-linked ubiquitination of RBPMS to increase its proteasomal degradation and activator protein 1 (AP-1) transactivation. Impairments in RBPMS function reverse the inhibitory effect of SH3RF2 depletion on cisplatin resistance. Collectively, the SH3RF2-RBPMS-AP-1 axis is an important regulator in cisplatin resistance and inhibition of SH3RF2 may be a potential target in preventing cisplatin resistance.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2025
·
IF 1.7
Qiu Yu,Ruan Huijie,Ji Decai,Cao Na
Bladder cancer is a common malignancy in the genitourinary system with its incidence rate among the world's highest. Neuralized E3 ubiquitin protein ligase 1 (NEURL1) belongs to the RING E3 ubiquitin ligase family, and its role in bladder cancer has not been reported yet. We aimed to explore the expression and roles of NEURL1 in bladder cancer. The NEURL1 expression was determined in clinical samples of bladder cancer. We stably overexpressed NEURL1 and NEURL1 with the RING domain deletion in human bladder cancer cell lines 5637 and RT-112 to investigate its functions. NEURL1 was confirmed to be significantly down-regulated in clinical bladder tumor specimens. NEURL1 overexpression significantly inhibited the growth, colony formation, and Ki-67 protein expression in both bladder cancer cells. The overexpression of NEURL1 also increased the apoptosis rate and cleaved caspase-3 protein expression in 5637 and RT-112 cells. As expected, the RING-deleted NEURL1 had no such effect. Moreover, NEURL1 overexpression facilitated the apoptosis of 5637/RT-112 cells under cisplatin conditions. NEURL1 promotes ubiquitination and proteasomal degradation of PDE9A. PDE9A protein expression was notably increased in bladder tumors from clinical specimens. Overexpressed NEURL1 inhibited PDE9A protein expression in both cell lines, whereas NEURL1 with the RING domain deletion did not. The addition of proteasome inhibitors MG-132 reversed the decrease in PDE9A expression by NEURL1 overexpression. Cell viability was inhibited and apoptosis was increased in the 5637 and RT-112 cells with stable knockdown of PDE9A. NEURL1 may be involved in the bladder cancer progression by increasing apoptosis, thereby leading to tumor cell growth inhibition.
研究领域:
肿瘤学
·
分子生物学
·
泌尿外科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）