• oncogene proteins
• ubiquitins

• Glyoxylate cycle
• Gut microbiota
• HLA DR on HSC
• Immune cell
• Single-cell RNA sequencing

• Osteoporosis/genetics
• Osteoporosis/immunology
• Osteoporosis/microbiology
• Humans
• Gastrointestinal Microbiome/genetics
• Gastrointestinal Microbiome/immunology
• Computational Biology
• Mendelian Randomization Analysis
• Single-Cell Analysis
• Sequence Analysis, RNA
• Multiomics

• Cancer hallmarks
• Colorectal cancer (CRC)
• DUBTACs
• Deubiquitinases
• E3 ubiquitin ligases
• PROTACs
• Signaling pathways

• Humans
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/enzymology
• Colorectal Neoplasms/therapy
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitin-Protein Ligases/genetics
• Deubiquitinating Enzymes/metabolism
• Wnt Signaling Pathway
• NF-kappa B/metabolism
• Ubiquitination
• Animals
• Signal Transduction

• CDK2 downregulation
• Colorectal cancer
• Extracellular vesicles
• MAGI2-AS3
• MYC protein translation modification
• USP6NL DNA methylation

• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/metabolism
• Extracellular Vesicles/metabolism
• Animals
• Mice
• Cell Proliferation
• Adaptor Proteins, Signal Transducing/metabolism
• Mesenchymal Stem Cells/metabolism
• Cell Line, Tumor
• Cell Movement
• Mice, Nude
• DNA Methylation
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Cyclin-Dependent Kinase 2/metabolism
• Proto-Oncogene Proteins c-myc/metabolism
• Mice, Inbred BALB C
• Guanylate Kinases

• Wnt/β-catenin signaling pathway
• colorectal carcinoma cells
• hawthorn proanthocyanidin
• network pharmacology

• YJ2020029 Hebei Agricultural University
• No.C2021204152 the Natural Science Foundation of Hebei Province
• KY2023045 the Basic Scientific Research Expenses of Universities in Hebei Province

• Biomarker discovery
• Colorectal cancer
• Deubiquitinase protein family
• Drug target discovery
• Ubiquitin-specific peptidases

• Wnt/β‑catenin signaling pathway
• colorectal cancer
• inhibitors
• occurrence
• recurrence
• targeted therapy

• Humans
• CDC2 Protein Kinase/antagonists & inhibitors
• Cell Line, Tumor
• Cyclin-Dependent Kinases/antagonists & inhibitors
• Proteolysis
• Proteomics
• Triple Negative Breast Neoplasms/drug therapy

• P50 CA186786 NCI NIH HHS
• R35 CA231996 NCI NIH HHS
• National Institutes of Health
• Government of Guangdong Province
• LIVZON pharm
• National Natural Science Foundation of China
• Prostate Cancer Foundation
• National Cancer Institute

This review summarizes the current DUBs findings that correlate with the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The DUBs were further classified by their biological functions in terms of proliferation, metastasis, and apoptosis. The work provides an updated of the current findings, and could be used as a quick guide for researchers to identify target DUBs in cancers.

Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers.

Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30–60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment modalities and higher recurrence rates. The drug resistance observed is associated with multiple genetic or epigenetic factors. The ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) is a GTPase-activating protein that functions as a deubiquitinating enzyme and regulates endocytosis and signal transduction. It is highly expressed in many cancer types and may promote the growth and proliferation of cancer cells. We hypothesized that USP6NL affects GBM chemoresistance and tumorigenesis, and that its inhibition may be a novel therapeutic strategy for GBM treatment. The USP6NL level, together with EGFR expression in human GBM tissue samples and cell lines associated with therapy resistance, tumor growth, and cancer invasion, were investigated. Its pivotal roles and potential mechanism in modulating tumor growth, and the key mechanism associated with therapy resistance of GBM cells, were studied, both in vitro and in vivo. Herein, we found that deubiquitinase USP6NL and growth factor receptor EGFR were strongly associated with the oncogenicity and resistance of GBM, both in vitro and in vivo, toward temozolomide, as evidenced by enhanced migration, invasion, and acquisition of a highly invasive and drug-resistant phenotype by the GBM cells. Furthermore, abrogation of USP6NL reversed the properties of GBM cells and resensitized them toward temozolomide by enhancing autophagy and reducing the DNA damage repair response. Our results provide novel insights into the probable mechanism through which USP6NL/EGFR signaling might suppress the anticancer therapeutic response, induce cancer invasiveness, and facilitate reduced sensitivity to temozolomide treatment in GBM in an autolysosome-dependent manner. Therefore, controlling the USP6NL may offer an alternative, but efficient, therapeutic strategy for targeting and eradicating otherwise resistant and recurrent phenotypes of aggressive GBM cells.

• Cornell Feline Health Center
• Hill's Pet Nutrition
• National Institutes of Health
• College of Veterinary Medicine, Cornell University

• Colorectal cancer
• Expression
• Prognosis
• Risk
• XPF

Schistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/β-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.

• DUB inhibitors
• cancer stem cells
• deubiquitinating enzymes
• signaling
• stemness

• 2018M3A9H3022412 National Research Foundation of Korea

Triple-negative breast cancer (TNBC), in part because of the high metastasis rate, is one of the most prevalent causes of malignancy-related mortality globally. Ubiquitin specific peptidase 6 N-terminal like (USP6NL) has been unmasked to be implicated in some human cancers. However, the precise biological function of USP6NL in TNBC has not been defined.

RNA expression was examined by real-time quantitative PCR (RT-qPCR), while USP6NL protein level was tested through western blot. Besides, cell proliferation was assessed by using colony formation assay, whereas cell apoptosis estimated by flow cytometry analysis, JC-1 assay and TUNEL assay. Transwell assays were adopted to detect the migration and invasion of indicated TNBC cells. Immunofluorescence (IF) assay evaluated epithelial-mesenchymal transitions (EMT) progress in TNBC. Further, RNA immunoprecipitation (RIP), RNA pull down and luciferase reporter assays were implemented for measuring the mutual interplay among USP6NL, miR-142-3p and long intergenic non-protein coding RNA 689 (LINC00689).

Elevated USP6NL level was uncovered in TNBC cells. RNA interference-mediated knockdown of USP6NL inhibited TNBC cell growth, motility and EMT. Further, USP6NL was proved as the target of a tumor-inhibitor miR-142-3p, and LINC00689 augmented USP6NL expression by absorbing miR-142-3p. Importantly, miR-142-3p deficiency or USP6NL overexpression fully abolished the inhibitory effect of LINC00689 silence on TNBC cellular behaviors.

All data revealed the important role of USP6NL/LINC00689/miR-142-3p signaling in TNBC. The findings might provide a new and promising therapeutic biomarker for treating patients with TNBC.

• LINC00689
• Triple-negative breast cancer
• USP6NL
• miR-142-3p

The Wnt signaling pathway plays important roles in embryonic development, homeostatic processes, cell differentiation, cell polarity, cell proliferation, and cell migration via the β-catenin binding of Wnt target genes. Dysregulation of Wnt signaling is associated with various diseases such as cancer, aging, Alzheimer’s disease, metabolic disease, and pigmentation disorders. Numerous studies entailing the Wnt signaling pathway have been conducted for various cancers. Diverse signaling factors mediate the up- or down-regulation of Wnt signaling through post-translational modifications (PTMs), and aberrant regulation is associated with several different malignancies in humans. Of the numerous PTMs involved, most Wnt signaling factors are regulated by ubiquitination and deubiquitination. Ubiquitination by E3 ligase attaches ubiquitins to target proteins and usually induces proteasomal degradation of Wnt signaling factors such as β-catenin, Axin, GSK3, and Dvl. Conversely, deubiquitination induced by the deubiquitinating enzymes (DUBs) detaches the ubiquitins and modulates the stability of signaling factors. In this review, we discuss the effects of ubiquitination and deubiquitination on the Wnt signaling pathway, and the inhibitors of DUBs that can be applied for cancer therapeutic strategies.

• Wnt signaling
• cancer
• deubiquitinating enzymes
• inhibitor
• small molecules
• ubiquitination

Deubiquitinases (DUBs) are involved in various cellular functions. They deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. Studies on the roles of deubiquitylation have been conducted in various cancers to identify the carcinogenic roles of DUBs. In this review, we evaluate the biological roles of DUBs in cancer, including proliferation, cell cycle control, apoptosis, the DNA damage response, tumor suppression, oncogenesis, and metastasis. This review mainly focuses on the regulation of different downstream effectors and pathways via biochemical regulation and posttranslational modifications. We summarize the relationship between DUBs and human cancers and discuss the potential of DUBs as therapeutic targets for cancer treatment. This review also provides basic knowledge of DUBs in the development of cancers and highlights the importance of DUBs in cancer biology.

• cancer
• degradation
• deubiquitinase
• therapeutic target

• Animals
• Apoptosis/genetics
• Biomarkers
• Biomarkers, Tumor
• Cell Cycle/genetics
• Cell Proliferation/genetics
• Deubiquitinating Enzymes/genetics
• Deubiquitinating Enzymes/metabolism
• Disease Management
• Disease Susceptibility
• Humans
• Molecular Targeted Therapy
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/therapy
• Oncogenes

Upregulated ubiquitin-conjugating enzyme E2M (UBE2M) is associated with poor prognosis in malignancies; However, the phenotype and mechanism of action of UBE2M in hepatocellular carcinoma (HCC) remain elusive. Here, we report that UBE2M is overexpressed and correlated with poor prognosis in HCC patients. The UBE2M level is an independent prognostic factor for HCC patients. UBE2M knockdown inhibits HCC cell proliferation, migration, and invasion, whereas its overexpression has an opposite effect. Mechanistically, upregulated UBE2M exerts oncogenic effects by translocation of accumulated β-catenin from the cytoplasm to the nucleus, thus activating downstream β-catenin/cyclin D1 signaling. In summary, our study demonstrates a notable role of UBE2M in promoting the growth of HCC, providing a novel strategy for HCC prevention and treatment.

• hepatocellular carcinoma
• prognosis
• proliferation
• ubiquitin-conjugating enzyme E2M
• β-catenin

• Esophageal squamous cell carcinoma
• Wnt/β-catenin signaling pathway
• kallikrein-associated peptidase 11
• proliferation