BIOLOGICAL PROCEDURES ONLINE
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2024
·Vol. 26
·期 1
·1-18
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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
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分子生物学
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细胞生物学
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癌症研究
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高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
He Xin,Chuanzhuo Wang,Yuan Chi,Zhaoyu Liu
Colorectal cancer is a common malignant tumor worldwide. Ubiquitin-specific proteases 53 (USP53) is a deubiquitinase that plays tumor-suppressing roles in multiple cancers. The analysis from databank showed that USP53 was downregulated in colorectal cancer specimens, and patients with USP53 low expression displayed poorer survival. This study aims to investigate the role of USP53 in colorectal cancer. Our clinical data displayed the low expression of USP53, compared with paired para-carcinoma tissues. Gain- and loss-of-function experiments firstly demonstrated that the overexpression of USP53 suppressed growth of colorectal cancer cells in vivo and in vitro , and aggravated bleomycin-induced cell damage. The silencing of USP53 played opposite roles. Through immunoprecipitation-liquid chromatogram/mass spectrum (IP-LC/MS) and ubiquitylome analysis, mortality factor 4-like protein 1 (MORF4L1) was screened as the potential substrate of USP53. The USP53 and MORF4L1 protein levels were positively related in colorectal cancer samples. USP53 bound to MORF4L1 and intercepted its ubiquitination and degradation, and the K249 and K227 of MORF4L1 protein were identified as the key sites. MORF4L1 was decreased in colorectal cancer samples, and patients with low MORF4L1 expression also exhibited poorer survival. Enhanced expression of MORF4L1 alleviated proliferation of colorectal cancer cells, and the effects of shUSP53 on colorectal cancer cells were abrogated by MORF4L1. In conclusion, USP53 suppressed growth of colorectal cancer cells by catalyzing the deubiquitination of MORF4L1. These findings may provide novel diagnostic markers or therapeutic targets for colorectal cancer in clinic.
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高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2026
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IF 5
Guihong Li,Ting Lei,Erpeng Liu,Jing Shen,Dun Liu,Xuqiang Zhu
USP53 upregulation is identified as an independent risk factor for GBM progression. • USP53 upregulation is associated with poor prognosis of GBM patients. • USP53 promotes cell growth and the tumorigenicity of GBM cells. • USP53 removes ubiquitination from ALKBH5 and enhances its stability. • ALKBH5 removes the m6A modification of TERT and increases its RNA stability. Glioblastoma (GBM) is the most common malignant glioma, with a high recurrence rate and a poor prognosis. Deubiquitinating enzyme ubiquitin-specific peptidase 53 (USP53), known to enhance the stability of downstream proteins, exhibits distinct functions in different tumors. The function of USP53 in GBM progression remains unclear. Analysis of GSE104267 and GSE4290 datasets revealed significant USP53 upregulation in GBM tissues, a finding confirmed by TCGA data comparing GBM ( n = 163) with normal brain tissues ( n = 207). In univariate and multivariate cox regression analysis, USP53 was identified as an independent risk factor (univariate, hazard ratio (HR) =1.5357, p = 0.0229; multivariate, HR =1.4851, p = 0.0385) for GBM progression. Patients with high expression of USP53 had worse prognosis compared to those with low expression of USP53. Functionally, USP53 knockdown potently inhibited proliferation and induced apoptosis in LN229 and A172 cells in vitro and attenuated tumorigenicity of LN229 cells in vivo . Conversely, forced expression of USP53 had a carcinogenic effect. Mechanistically, USP53 targeted ALKB homolog 5 (ALKBH5) for deubiquitination, thereby stabilizing the protein and prolonging its half-life. Restoring ALKBH5 expression rescued the proliferative deficit in USP53-silenced LN229 cells. Telomerase catalytic subunit telomerase reverse transcriptase (TERT) was identified as a downstream effector of the USP53/ALKBH5 axis, where ALKBH5 upregulated TERT RNA expression by erasing m6A modifications at position 1989 bp on TERT mRNA. Collectively, those observations demonstrate that USP53/ALKBH5 axis drives GBM progression by targeting TERT, indicating that USP53/ALKBH5 axis may serve as a potential therapeutic target for GBM. Download: Download high-res image (229KB) Download: Download full-size image
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高影响因子
MOLECULAR AND CELLULAR PROBES
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2025
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IF 3
Hongbo Lan,Lina Peng,Fei Chen,Kun Xie,Futing Mu,Jingshuang Wang,Juanjuan Mei,Wenhui Yan
Background Breast cancer (BC) remains the most common malignancy affecting women’s health globally. Thus, elucidating the molecular mechanisms driving BC progression and identifying novel therapeutic targets is imperative. Ubiquitin-specific peptidase 53 (USP53) is a deubiquitinating enzyme reported to exert tumor-suppressive effects in several types of cancers. However, USP53 has been poorly studied in BC. Methods Based on the TCGA database and GTEx transcriptome data, differentially expressed genes in BC were screened, and the relationship between USP53 expression and BC characteristics and prognosis were analyzed. qRT-PCR, western blot, and immunohistochemistry determined USP53 expression. After transfection, BC cells’ proliferation, migration, and invasion were assessed using CCK-8 and Transwell assay. A subcutaneous xenograft tumor model in nude mice was used to evaluate the in vivo effect of USP53. Besides, USP53 expression-associated immune cells were screened using the Cibersort package. Results USP53 expression was reduced in BC patients and showed potential diagnostic significance. Functionally, overexpressing USP53 inhibited BC cell proliferation, migration, and invasion, while silencing it promoted these malignant behaviors. In vivo , tumors derived from USP53-overexpressing cells grew more slowly and exhibited lower Ki67 expression. Additionally, we found that Tcm, T helper cells, Mast cells, and Eosinophils were positively associated with USP53 expression, whereas NK CD56dim cells and TReg were negatively associated with USP53 expression. Conclusions Together, we proved that USP53 was down-regulated in BC and weakened the malignant progression of BC cells both in vitro and in vivo . USP53 was also associated with a variety of immune cells. Our study suggested that USP53 may be a novel target for BC therapy.
研究领域:
肿瘤学
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分子生物学
·
免疫学
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遗传学
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生物信息学
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细胞生物学
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高影响因子
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