Scientific Reports
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2025
·Vol. 15
·期 1
·1-12
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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
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分子生物学
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细胞生物学
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Advanced Science
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2025
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IF 14.1
Aoyu Fan,Yunyan Zhang,Yunpeng Li,Wei Meng,Fan Wu,Wei Pan,Zhongliang Ma,Wei Chen
Prostate cancer (PCa) is one of the most common malignancies for male individuals globally. Androgen deprivation therapy (ADT) initially demonstrated significant efficacy in treating PCa; however, most cases of PCa eventually progress to castration-resistant prostate cancer (CRPC), which becomes increasingly challenging to manage. Notably, the loss or disruption of primary cilia in PCa cells may play a critical role in the progression of the disease, and there are no reports on the role of circular RNAs in ciliogenesis. Thus, this warrants further investigation.In this study, key circular RNAs linked to prostate cancer progression, and enzalutamide resistance is identified. Specifically, it is found that hsa_circ_0005185 interacts with OTUB1 and RAB8A, serving as a molecular scaffold. Hsa_circ_0005185 mediates the binding of the deubiquitinase OTUB1 to RAB8A, resulting in the deubiquitination of RAB8A. Consequently, the stable expression of RAB8A promotes the regeneration of primary cilia and enhances the production of GLI3R, an inhibitory factor in the Hedgehog signaling pathway, thereby suppressing AR activity and slowing the progression of CRPC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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信号转导
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Journal of Translational Medicine
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2025
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IF 7.5
Ying Feng,Jiamei Yue,Si Fan,Jiayan Wu
Background EMS (Endometriosis) is characterized by the presence of functional endometrial tissue outside the uterus and is one of the most common gynecological disorders. SOX18 (SYR-related high-mobility group box 18) is a transcription factor whose expression is higher in ectopic endometrial tissues than in eutopic endometrial tissues. However, its role in EMS has not been confirmed. Methods Here, immunohistochemistry (IHC) staining was used to analyze the expression pattern of SOX18 in EMS. Next, the effects of SOX18 on cell viability, migration and invasion were investigated. Dual-luciferase reporter assay, chromatin-immunoprecipitation (ch-IP) and DNA pull-down were employed to verify SOX18 binding to the OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) promoter. In addition, co-immunoprecipitation (co-IP) was used to analyze the binding of OTUB1 to YAP1 (Yes-associated protein 1). Allograft mouse model of EMS was established to explore the role of SOX18 in vivo. Results In vitro results demonstrated that upregulation of SOX18 promoted the proliferation, migration and invasion of Ishikawa cells and induced the EMT process, while knockdown of SOX18 showed the opposite effect. In vivo results also confirmed that SOX18 overexpression led to the deterioration of EMS, as reflected by significant pathological changes in mice. Mechanistically, our data proved that SOX18 directly bound to the OTUB1 promoter region and activated its transcription. Further investigation demonstrated that OTUB1 deubiquitinated YAP1 and enhanced its protein stability. Rescue experiments suggested that SOX18 modulated YAP1 expression through upregulating OTUB1, indicating the role of SOX18-OTUB1-YAP1 axis in EMS. Conclusions These discoveries underscore that SOX18 contributes to the pathogenesis of EMS through promoting OTUB1 transcription and activating Hippo/YAP1 signaling pathway, which may provide a new therapeutic target for EMS. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-025-06677-y.
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Antioxidants
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2025
·Vol. 14
·期 6
·698
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IF 6.6
Ziyun Hu,Yuxin Li,Di Xu,Huihui Meng,Wenya Liu,Qian Xu,Benxing Yao,Junsong Wang
Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, plays a crucial role in acetaminophen (APAP)-induced hepatotoxicity. While 4-octyl itaconate (4-OI) demonstrates protective effects against APAP toxicity, its molecular mechanisms remain to be fully elucidated. Through an innovative integration of untargeted metabolomics and pathway analysis, we unveil a novel dual mechanism by which 4-OI prevents APAP-induced ferroptosis. We discovered that 4-OI stabilizes SLC7A11 through OTUB1-mediated deubiquitination, thereby restoring cystine import and glutathione (GSH) synthesis. In addition, 4-OI activates the Nrf2 pathway, orchestrating a comprehensive antioxidant response by upregulating the key proteins involved in both glutathione metabolism and iron homeostasis, including GPX4, FTH1, FTL1, and FPN1. This coordinated action effectively prevents the accumulation of toxic iron and lipid peroxides. Our findings not only elucidate the protective mechanisms of 4-OI but also establish it as a promising therapeutic candidate for ferroptosis-related diseases through its unique ability to simultaneously modulate the SLC7A11-GPX4 antioxidant axis and iron homeostasis.
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Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-14
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IF 9.6
Zhang Pengchao,Cheng Jian,Liu Zhao,Adeshakin Funmilayo O.,Dai Liujiang,Niu Xiangyun,Zhang Ziyang,Peng Xixia,Li Long,Liu Maoxuan,Yan Dehong,Yang Xiaolu,Wan Xiaochun,Zhang Guizhong
Anoikis resistance, an essential prerequisite for tumor metastasis, is now recognized as a promising target in the fight against tumor progression. However, the detailed mechanisms of anoikis resistance are not fully understood, and drugs targeting anoikis resistance are not currently available. Here we report that NY-ESO-1, a well-known cancer-testis antigen, is linked to a poor prognosis in tumor patients and that it is crucial for anoikis resistance and tumor metastasis. Overexpression of NY-ESO-1 in cancer cells enhanced ERK1/2 activation, which in turn promoted resistance to anoikis, increased colony formation in soft agar, and facilitated lung metastasis in mice. Conversely, NY-ESO-1 knockdown significantly reduced ERK1/2 activity, leading to enhanced anoikis, diminished colony formation, and impaired metastatic potential. Mechanistically, NY-ESO-1 acts as a scaffold protein to recruit the deubiquitinase OTUB1 to PP1α, forming a ternary complex that prevents PP1α from being ubiquitinated. The OTUB1’s deubiquitinase activity, not its ability to suppress E2 enzymes, is necessary for reducing polyubiquitination and improving PP1α stability. Finally, accumulated PP1α proteins significantly activate downstream ERK1/2. Blockade of ERK1/2 or knocking down PP1α antagonized NY-ESO-1-mediated anoikis resistance. These results not only reveal a previously unrecognized mode for deubiquitinase substrate expansion but also highlight the function of NY-ESO-1 in anoikis resistance and suggest NY-ESO-1 as a novel attractive target for preventing tumor metastasis.
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CELLULAR SIGNALLING
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2023
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IF 4.8
Yunyun Li,Ruizhe Li,Hui Qin,Hongliu He,Shanshan Li
Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), a deubiquitinating enzyme known to regulate the stability of downstream proteins, has been reported to regulate various cancers tumorigenesis, yet its direct effects on oral squamous cell carcinoma (OSCC) progression are unclear. Bioinformatics analysis was performed to screen for genes of interest, and in vitro and in vivo studies were carried out to investigate the function and mechanism of OTUB1 in OSCC. We found that OTUB1 was abnormally elevated in OSCC tissues and positively associated with the pathological stage and tumor stage. Knockdown of OTUB1 impaired the malignance of OSCC cells - suppressed cell proliferation, invasion, migration, and xenografted tumor growth. OTUB1 silencing also drove tumor-associated macrophage M1 polarization but suppressed M2 polarization, and the induction of M1 polarization inhibited the survival of OSCC cells. However, OTUB1 overexpression exerted the opposite effects. Furthermore, the protein network that interacted with the OTUB1 protein was constructed based on the GeneMANIA website. Receptor for activated C kinase 1 (RACK1), a facilitator of OSCC progression, was identified as a potential target of the OTUB1 protein. We revealed that OTUB1 positively regulated RACK1 expression and inhibited RACK1 ubiquitination. Additionally, RACK1 upregulation reversed the effects of OTUB1 knockdown on OSCC progression. Overall, we demonstrated that OTUB1 might regulate OSCC progression by maintaining the stability of the RACK1 protein. These findings highlight the potential roles of the OTUB1/RACK1 axis as a potential therapeutic target in OSCC.
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