Knockdown of UCHL3 inhibits esophageal squamous cell carcinoma progression by reducing CRY2 methylation

Xue, Jijun; Yi, Jinyuan; Zhu, Xiaolong

doi:10.1007/s13577-021-00660-7

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…Previously, UCHL3 has been found to be robustly expressed in epithelial ovarian cancer and related to intra-abdominal metastases [29]. UCHL3 has been described as a tumor promoter that regulates DNA methylation, chromosome stability, and DNA repair in different types of malignancies [30][31][32][33]. UCHL3 encodes a protein characterized by deubiquitylating activity.…”

Section: Discussionmentioning

confidence: 99%

Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression

Liu,

Fan,

Xie

et al. 2023

J Transl Med

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Background The catenin beta 1 gene (CTNNB1) plays a crucial role in the malignant progression of various cancers. Recent studies have suggested that CTNNB1 hyperactivation is closely related to the occurrence and development of bladder cancer (BCa). As a member of the deubiquitinating enzyme (DUB) family, ubiquitin C-terminal hydrolase L3 (UCHL3) is abnormally expressed in various cancers. In this study, we discovered that UCHL3 is a novel oncogene in bladder cancer, suggesting it is a promising target against bladder cancer. Methods We utilized CRISPR‒Cas9 technology to construct cell lines with UCHL3 stably overexpressed or knocked out. The successful overexpression or knockout of UCHL3 was determined using Western blotting. Then, we performed CCK-8, colony formation, soft agar and Transwell migration assays to determine the impact of the UCHL3 gene on cell phenotype. RNA-seq was performed with UCHL3-depleted T24 cells (established via CRISPR–Cas9-mediated genomic editing). We analyzed differences in WNT pathway gene expression in wild-type and UCHL3-deficient T24 cell lines using a heatmap and by gene set enrichment analysis (GSEA). Then, we validated the effect of UCHL3 on the Wnt pathway using a dual fluorescence reporter. We then analyzed the underlying mechanisms involved using Western blots, co-IP, and immunofluorescence results. We also conducted nude mouse tumor formation experiments. Moreover, conditional UCHL3-knockout mice and bladder cancer model mice were established for research. Results We found that the overexpression of UCHL3 boosted bladder cancer cell proliferation, invasion and migration, while the depletion of UCHL3 in bladder cancer cells delayed tumor tumorigenesis in vitro and in vivo. UCHL3 was highly associated with the Wnt signaling pathway and triggered the activation of the Wnt signaling pathway, which showed that its functions depend on its deubiquitination activity. Notably, Uchl3-deficient mice were less susceptible to bladder tumorigenesis. Additionally, UCHL3 was highly expressed in bladder cancer cells and associated with indicators of advanced clinicopathology. Conclusion In summary, we found that UCHL3 is amplified in bladder cancer and functions as a tumor promoter that enhances proliferation and migration of tumor cells in vitro and bladder tumorigenesis and progression in vivo. Furthermore, we revealed that UCHL3 stabilizes CTNNB1 expression, resulting in the activation of the oncogenic Wnt signaling pathway. Therefore, our findings strongly suggest that UCHL3 is a promising therapeutic target for bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression

Liu,

Fan,

Xie

et al. 2023

J Transl Med

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“…In addition, several E2, E3, and DUB enzymes have been identified with protumorigenic or anticancer effects in GBM/GSCs [22]. UCHL3 is a significant member of the UCL subfamily that modulates numerous cellular processes, including cell viability and invasion [23,24]. DNA damage repair and radioresistance [25][26][27], and stemness maintenance [28].…”

Section: Introductionmentioning

confidence: 99%

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells

Fan,

You,

Jiang

et al. 2024

Cell. Mol. Life Sci.

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Background The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. Method Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. Result We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. Conclusion These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

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“…However, its involvement in osteoporosis remains unclear. On the other hand, cryptochrome 2 (CRY2) is a core component of clock proteins and is associated with DNA damage and repair, cell proliferation, and tumorigenesis [ 27 , 28 ]. It has been implicated in the regulation of osteoporosis, with evidence suggesting its participation in osteogenic differentiation [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

CircZNF367 promotes osteoclast differentiation and osteoporosis by interacting with FUS to maintain CRY2 mRNA stability

Deng

Wang

Luo³

et al. 2023

J Orthop Surg Res

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Background Osteoporosis, characterized by reduced bone mass and deterioration of bone quality, is a significant health concern for postmenopausal women. Considering that the specific role of circRNAs in osteoporosis and osteoclast differentiation remains poorly understood, this study aims to shed light on their involvement in these processes to enhance our understanding and potentially contribute to improved treatment strategies for osteoporosis. Methods An osteoporotic model was constructed in vivo in ovariectomized mouse. In vitro, we induced osteoclast formation in bone marrow-derived macrophages (BMDMs) using M-CSF + RANKL. To assess osteoporosis in mice, we conducted HE staining. We used MTT and TRAP staining to measure cell viability and osteoclast formation, respectively, and also evaluated their mRNA and protein expression levels. In addition, RNA pull-down, RIP and luciferase reporter assays were performed to investigate interactions, and ChIP assay was used to examine the impact of circZNF367 knockdown on the binding between FUS and CRY2. Results We observed increased expression of CircZNF367, FUS and CRY2 in osteoporotic mice and M-CSF + RANKL-induced BMDMs. Functionally, knocking down circZNF367 inhibited osteoporosis in vivo. Furthermore, interference with circZNF367 suppressed osteoclast proliferation and the expression of TRAP, NFATc1, and c-FOS. Mechanistically, circZNF367 interacted with FUS to maintain CRY2 mRNA stability. Additionally, knocking down CRY2 rescued M-CSF + RANKL-induced osteoclast differentiation in BMDMs promoted by circZNF367 and FUS. Conclusion This study reveals that the circZNF367/FUS axis may accelerate osteoclasts differentiation by upregulating CRY2 in osteoporosis and suggests that targeting circZNF367 may have potential therapeutic effects on osteoporosis.

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Knockdown of UCHL3 inhibits esophageal squamous cell carcinoma progression by reducing CRY2 methylation

Cited by 6 publications

References 37 publications

Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression

Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells

CircZNF367 promotes osteoclast differentiation and osteoporosis by interacting with FUS to maintain CRY2 mRNA stability

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