• Gene transcription
• Histone modification inhibitors
• Histone modifications
• Histone-modifying enzymes
• Thyroid cancer

• Humans
• Thyroid Neoplasms/drug therapy
• Thyroid Neoplasms/metabolism
• Thyroid Neoplasms/pathology
• Histones/metabolism
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Protein Processing, Post-Translational/drug effects
• Histone Deacetylase Inhibitors/therapeutic use

• HDAC
• HMTs
• KDMs
• acetylation
• cancer
• histone PTMs
• methylation

• Humans
• Neoplasms/immunology
• Neoplasms/therapy
• Neoplasms/metabolism
• Protein Processing, Post-Translational
• Histones/metabolism
• Animals
• Epigenesis, Genetic
• Histone Code
• Gene Expression Regulation, Neoplastic

• cell biology
• cancer

• WI 5171/1-1 Deutsche Forschungsgemeinschaft (German Research Foundation)
• WI 5171/4-1 Deutsche Forschungsgemeinschaft (German Research Foundation)
• FU 436/20-1 Deutsche Forschungsgemeinschaft (German Research Foundation)
• FU 436/21-1 Deutsche Forschungsgemeinschaft (German Research Foundation)
• WI 5171/3-2 Deutsche Forschungsgemeinschaft (German Research Foundation)
• 70113680 Deutsche Krebshilfe (German Cancer Aid)
• 2020.008.1 Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)
• Frankfurter Stiftung für krebskranke Kinder Dr. Eberhard and Hilde Rüdiger Foundation

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

• DNA Breaks, Double-Stranded
• DNA Repair
• Mutation
• Protein Processing, Post-Translational
• Recombinational DNA Repair

• National Natural Science Foundation of China
• Foundation for Innovative Research Groups of the National Natural Science Foundation of China
• National Key Research and Development Program of China Stem Cell and Translational Research
• West China Hospital, Sichuan University

• acetylation
• cancer
• methylation
• phosphorylation
• post‐translational modifications

• Cancer
• Genome instability
• H2B
• Transcription
• Ubiquitination

• cell signalling
• inflammation

Histone epigenetic modification disorder is an important predisposing factor for the occurrence and development of many cancers, including colorectal cancer (CRC). The role of MYSM1, a metalloprotease that deubiquitinates monoubiquitinated histone H2A, in colorectal cancer was identified to evaluate its potential clinical application value.

MYSM1 expression levels in CRC cell lines and tumor tissues were detected, and their associations with patient survival rate and clinical stage were analyzed using databases and tissue microarrays. Gain- and loss-of-function studies were performed to identify the roles of MYSM1 in CRC cell proliferation, apoptosis, cell cycle progression, epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo. ChIP, rescue assays and signal pathway verification were conducted for mechanistic study. Immunohistochemistry (IHC) was used to further assess the relationship of MYSM1 with CRC diagnosis and prognosis.

MYSM1 was significantly downregulated and was related to the overall survival (OS) of CRC patients. MYSM1 served as a CRC suppressor by inducing apoptosis and inhibiting cell proliferation, EMT, tumorigenic potential and metastasis. Mechanistically, MYSM1 directly bound to the promoter region of miR-200/CDH1, impaired the enrichment of repressive H2AK119ub1 modification and epigenetically enhanced miR-200/CDH1 expression. Testing of paired CRC patient samples confirmed the positive regulatory relationship between MYSM1 and miR-200/CDH1. Furthermore, silencing MYSM1 stimulated PI3K/AKT signaling and promoted EMT in CRC cells. More importantly, a positive association existed between MYSM1 expression and a favorable CRC prognosis.

MYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis.

The online version contains supplementary material available at 10.1186/s13046-021-02106-2.

• Colorectal cancer
• EMT
• MYSM1
• PI3K/AKT
• miR-200

• Cell cycle regulation
• Deubiquitination
• Immune microenvironment
• Neoplasms
• Stemness maintenance

• BUB1
• H2B ubiquitination
• H2Bub1
• STED
• USP22
• cancer
• chromatin compaction
• chromosome instability
• mitosis
• quantitative imaging microscopy

• 162374 CIHR

• RIPK1
• cancer
• mixed lineage kinase domain-like
• post-translational modifications
• ubiquitin hydrolase

• Apoptosis/genetics
• Humans
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Necroptosis
• Necrosis
• Receptor-Interacting Protein Serine-Threonine Kinases/genetics
• Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
• Signal Transduction
• Ubiquitin Thiolesterase
• Ubiquitination

• Deutsche Forschungsgemeinschaft (DFG)
• Bundesministerium für Bildung und Forschung (BMBF)

Aberrant expression of ubiquitin-specific peptide 22 (USP22) has been detected in various cancers. This study aimed to investigate the role of USP22 and the underlying mechanism in human gastric cancer.

The expression pattern of USP22 in human gastric cancer was detected in a tissue microarray containing 88 pairs of gastric cancer tissue and adjacent normal tissue samples from patients with primary gastric cancer using immunohistochemical staining. The correlation of USP22 expression with clinical characteristics of patients, as well as their prognostic values in the overall survival of patients, were evaluated. USP22-overexpressing SGC7901 and USP22-silencing AGS cells were used to explore the role of USP22 in gastric cancer cell behavior in vitro and in vivo. Chromatin immunoprecipitation was performed to identify differentially expressed genes induced by USP22 overexpression. Western blot analysis was conducted to detect the activation of RAS/ERK and PI3K/AKT signaling in USP22-overexpressing SGC7901 cells and xenograft tumor tissues. Knockdown of RAS activator son of sevenless 1 (SOS1) was performed to investigate the role of SOS1 in USP22-regulated gastric cancer cell behavior and RAS signaling both in vitro and in vivo.

USP22 protein expression was significantly increased in human gastric cancer tissues, compared with adjacent normal tissues, and was positively correlated with local tumor stage. Gain- and loss-of-function assays showed that USP22 promoted gastric cancer cell growth and cell cycle transition while suppressing apoptosis in vitro. Consistent results were observed in a xenograft mouse model. Chromatin immunoprecipitation revealed that the overexpression of USP22 induced the upregulation of RAS activator son of sevenless 1 (SOS1) in SGC7901 cells. Western blot analysis showed that USP22 overexpression also induced activation of the RAS/ERK and PI3K/AKT pathways in SGC7901 cells and xenograft tumor tissues. Furthermore, SOS1 silencing could reverse the effects of USP22 on gastric cancer cell behavior and RAS signaling both in vitro and in vivo.

Our results suggest that USP22 acts as an oncogene in gastric cancer in a SOS1-dependent manner, identifying the USP22/SOS1/RAS axis as a potential therapeutic target in gastric cancer.

• Gastric cancer
• RAS protein
• Son of sevenless 1
• Ubiquitin-specific peptide 22

N6-isopentenyladenosine has been shown to exert potent in vitro antitumor activity on different human cancers, including colorectal cancer. Although some potential biochemical targets have been identified, its precise mechanism of action remains unclear. We found that N6-isopentenyladenosine affects colorectal cancer proliferation in in vitro models carrying different mutational status of FBXW7 and TP53 genes, and in HCT116 xenografts in SCID mice, by increasing the expression of the well-established tumor suppressor FBXW7, a component of the SCF-E3 ubiquitin ligase complex that promotes degradation of various oncoproteins and transcription factors, such as c-Myc, SREBP and Mcl1. Corroborating our previous studies, we identified for the first time the FBXW7/SREBP/FDPS axis as a target of the compound. Pull down of ubiquitinated proteins, immunoprecipitation and luciferase assays, reveal that through the increase of FBXW7/c-Myc binding, N6-isopentenyladenosine induces the ubiquitination of c-Myc, inhibiting its transcriptional activity. Moreover, in FBXW7- and TP53-wild type cells, N6-isopentenyladenosine strongly synergizes with 5-Fluorouracil to inhibit colon cancer growth in vitro. Our results provide novel insights into the molecular mechanism of N6-isopentenyladenosine, revealing its multi-targeting antitumor action, in vitro and in vivo. Restoring of FBXW7 tumor-suppressor represents a valid therapeutic tool, enabling N6-isopentenyladenosine as optimizable compound for patient-personalized therapies in colorectal cancer.

• 5-fluorouracil
• FBXW7
• N6-isopentenyladenosine
• chemoresistance
• colon cancer
• mevalonate pathway

Colon cancer is one of the most common malignant tumors in the world; however, the mechanism underlying the progression of colon cancer remains unclear. In the present study, the expression of ubiquitin-specific peptidase 22 (USP22) in paraffin sections of human colon cancer tissues and normal colon tissues were examined using immunohistochemistry. The human colon cancer cell lines HCT116 and HT29 were used for USP22 knockdown experiments, and functional assays were performed. The results demonstrated that compared with normal colon tissues, human colon cancer tissues exhibited upregulated expression of USP22 and this was associated with tumor lymph node metastasis and tumor stage in colon cancer tissues. In addition, upregulated expression of USP22 was significantly correlated with both lower relapse-free survival and lower overall survival rates in patients with colon cancer. When USP22 was silenced in colon cancer cell lines, this resulted in a decrease in cell proliferation and metastatic behaviors. Furthermore, Bmi-1 and Cyclin D2 were found to be positively regulated by USP22, which may have mediated the tumorigenic effects of USP22 in human colon cancer. The results of the present study may have significant implications for examining the underlying mechanisms of cancer development and the potential development of cancer therapeutics.

• colon cancer
• metastasis
• oncogene
• proliferation
• ubiquitin-specific peptidase 22

Ubiquitination regulates nearly every aspect of cellular events in eukaryotes. It modifies intracellular proteins with 76-amino acid polypeptide ubiquitin (Ub) and destines them for proteolysis or activity alteration. Ubiquitination is generally achieved by a tri-enzyme machinery involving ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3). E1 activates Ub and transfers it to the active cysteine site of E2 via a transesterification reaction. E3 coordinates with E2 to mediate isopeptide bond formation between Ub and substrate protein. The E1-E2-E3 cascade can create diverse types of Ub modifications, hence effecting distinct outcomes on the substrate proteins. Dysregulation of ubiquitination results in severe consequences and human diseases. There include cancers, developmental defects and immune disorders. In this review, we provide an overview of the ubiquitination machinery and discuss the recent progresses in the ubiquitination-mediated regulation of embryonic stem cell maintenance and cancer biology.

• colorectal cancer
• embryonic stem cells
• osteosarcoma
• ubiquitination

Histone ubiquitination is a critical epigenetic mechanism regulating DNA-driven processes such as gene transcription and DNA damage repair. Importantly, the cellular machinery regulating histone ubiquitination is frequently altered in cancers. Moreover, aberrant histone ubiquitination can drive oncogenesis by altering the expression of tumor suppressors and oncogenes, misregulating cellular differentiation and promoting cancer cell proliferation. Thus, targeting aberrant histone ubiquitination may be a viable strategy to reprogram transcription in cancer cells, in order to halt cellular proliferation and induce cell death, which is the basis for the ongoing development of therapies targeting histone ubiquitination. In this review, we present the normal functions of histone H2A and H2B ubiquitination and describe the role aberrant histone ubiquitination has in oncogenesis. We also describe the key benefits and challenges associated with current histone ubiquitination targeting strategies. As these strategies are predicted to have off-target effects, we discuss additional efforts aimed at developing synthetic lethal strategies and epigenome editing tools, which may prove pivotal in achieving effective and selective therapies targeting histone ubiquitination, and ultimately improving the lives and outcomes of those living with cancer.

• E3 ubiquitin ligase
• H2A
• H2B
• cancer
• deubiquitination
• epigenetic therapy
• epigenome editing
• histone
• synthetic lethality
• ubiquitination

• Animals
• DNA Damage
• DNA Repair
• Histones/metabolism
• Humans
• Molecular Targeted Therapy
• Neoplasms/metabolism
• Ubiquitination

The expression of USP22 has been demonstrated to play a pivotal role in solid tumors. However, the prognostic value of USP22 still remains unknown.

A systematic meta-analysis was performed to assess the prognostic value of USP22 in cancers. A literature collection was conducted from inception to June 8, 2017 by searching PubMed, Cochrane Library, Embase, Ovid and Web of Science databases. The pooled hazard ratio (HR) and odds ratio (OR) were used to correlate high expression of USP22 with overall survival (OS) and clinicopathological features.

The results, pooled by 19 studies with 2,876 cases, indicated that high expression of USP22 predicted poor OS (HR=2.48, 95% CI: 2.11–2.84, p<0.001) and disease-free survival (DFS; HR=2.55, 95% CI: 2.05–3.05, p<0.001) of cancer patients. Furthermore, high expression of USP22 was also significantly associated with advanced clinicopathological parameters, including tumor stage, tumor differentiation, metastasis, nodal status and tumor size.

Our finding revealed that USP22 might be an indicator of poor prognosis and advanced clinicopathological features of solid tumors and could be served as a novel biomarker.

• USP22
• biomarker
• carcinoma
• meta-analysis
• prognosis

• Deubiquitinating enzyme
• H2B
• H2Bub1
• Histone
• USP36

Ubiquitin-Specific Peptidase 22 (USP22) is a ubiquitin hydrolase, notably catalyzing the removal of the mono-ubiquitin moiety from histone H2B (H2Bub1). Frequent overexpression of USP22 has been observed in various cancer types and is associated with poor patient prognosis. Multiple mechanisms have been identified to explain how USP22 overexpression contributes to cancer progression, and thus, USP22 has been proposed as a novel drug target in cancer. However, gene re-sequencing data from numerous cancer types show that USP22 expression is frequently diminished, suggesting it may also harbor tumor suppressor-like properties. This review will examine the current state of knowledge on USP22 expression in cancers, describe its impact on H2Bub1 abundance and present the mechanisms through which altered USP22 expression may contribute to oncogenesis, including an emerging role for USP22 in the maintenance of genome stability in cancer. Clarifying the impact aberrant USP22 expression and abnormal H2Bub1 levels have in oncogenesis is critical before precision medicine therapies can be developed that either directly target USP22 overexpression or exploit the loss of USP22 expression in cancer cells.

• DNA double-strand break repair
• DUBm
• H2Bub1
• SAGA complex
• USP22
• cancer
• cell cycle regulation
• chromosome instability
• genome stability
• precision medicine

This meta-analysis study aimed to reveal the prognostic relevance of ubiquitin-specific protease 22 (USP22) expression in patients with cancers.

PubMed, Embase, and the Cochrane Library electronic databases were searched for relevant studies published up to April 2017. The prognostic value of USP22 expression was evaluated by hazard ratio with 95% confidence intervals (CIs). Relative risk (RR) with 95% CIs assessed the effects of USP22 expression on clinicopathological parameters. A total of 16 studies of 2,233 Chinese patients were included in the final meta-analysis.

A significant association was found between USP22 overexpression and survival in patients with cancers. The pooled RR indicated that USP22 overexpression was related to histological grade, advanced tumor–node–metastasis stage, positive lymph node metastasis, and distant metastasis.

This meta-analysis demonstrated that USP22 could be a novel biomarker for predicting prognosis in patients with cancers in the Chinese population.

• cancer
• meta-analysis
• prognosis
• survival
• ubiquitin-specific protease 22

• COX-2
• HCC
• HULC
• Tumor growth
• USP22

Monoubiquitylation of histone H2B (H2Bub1) is catalyzed mainly by the RNF20/RNF40 complex and erased by multiple deubiquitylating enzymes (DUBs). H2Bub1 influences many aspects of chromatin function, including transcription regulation and DNA repair. Cancer cells often display reduced levels of H2Bub1, and this reduction may contribute to cancer progression. The let-7 family of microRNAs comprises multiple members with reported tumor suppressive features, whose expression is frequently downregulated in cancer. We now report that let-7b and let-7c can positively regulate cellular H2Bub1 levels. Overexpression of let-7b and let-7c in a variety of non-transformed and cancer-derived cell lines results in H2Bub1 elevation. The positive effect of let-7b and let-7c on H2Bub1 levels is achieved through targeting of multiple mRNAs, coding for distinct components of the H2B deubiquitylation machinery. Specifically, let-7b and let-7c bind directly and inhibit the mRNAs encoding the DUBs USP42 and USP44, and also the mRNA encoding the adapter protein ATXN7L3, which is part of the DUB module of the SAGA complex. RNF20 knockdown strongly reduces H2Bub1 levels and increases the migration of non-transformed mammary epithelial cells and breast cancer-derived cells. Remarkably, overexpression of let-7b, which partly counteracts the effect of RNF20 knockdown on H2Bub1 levels, also reverses the pro-migratory effect of RNF20 knockdown. Likewise, ATXN7L3 knockdown also increases H2Bub1 levels and reduces cell migration, and this anti-migratory effect is abolished by simultaneous knockdown of RNF20. Together, our findings uncover a novel function of let-7 microRNAs as regulators of H2B ubiquitylation, suggesting an additional mechanism whereby these microRNAs can exert their tumor suppressive effects.

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Blotting, Western
• Cell Line, Tumor
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/physiopathology
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Neoplastic Processes
• Prognosis
• RNA Interference
• RNA, Small Interfering
• Trans-Activators
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Ubiquitin-Specific Proteases

• National Natural Science Foundation of China

• cancer
• deubiquitination
• deubiquitylation (deubiquitination)
• monoubiquitination
• non-degradative pathways
• polyubiquitin chain
• signal transduction
• therapeutic intervention
• ubiquitination
• ubiquitylation (ubiquitination)

Controlling cell proliferation is one of the hallmarks of cancer. A number of critical checkpoints ascertain progression through the different stages of the cell cycle, which can be aborted when perturbed, for instance by errors in DNA replication and repair. These molecular checkpoints are regulated by a number of proteins that need to be present at the right time and quantity. The ubiquitin system has emerged as a central player controlling the fate and function of such molecules such as cyclins, oncogenes and components of the DNA repair machinery. In particular, proteases that cleave ubiquitin chains, referred to as deubiquitylating enzymes (DUBs), have attracted recent attention due to their accessibility to modulation by small molecules. In this review, we describe recent evidence of the critical role of DUBs in aspects of cell cycle checkpoint control, associated DNA repair mechanisms and regulation of transcription, representing pathways altered in cancer. Therefore, DUBs involved in these processes emerge as potentially critical targets for the treatment of not only hematological, but potentially also solid tumors.

• DNA damage response
• cell cycle checkpoints
• deubiquitylating enzyme
• epigenetics
• multiple myeloma
• small molecule inhibitors
• transcription
• ubiquitin

Histone modifications play an important role in regulating access to DNA for transcription, DNA repair and DNA replication. A central player in these events is the mono-ubiquitylation of histone H2B (H2Bub1), which has been shown to regulate nucleosome dynamics. Previously, it was shown that H2Bub1 was important for nucleosome assembly onto nascent DNA at active replication forks. In the absence of H2Bub1, incomplete chromatin structures resulted in several replication defects. Here, we report new evidence, which shows that loss of H2Bub1 contributes to genomic instability in yeast. Specifically, we demonstrate that H2Bub1-deficient yeast accumulate mutations at a high frequency under conditions of replicative stress. This phenotype is due to an aberrant DNA Damage Tolerance (DDT) response upon fork stalling. We show that H2Bub1 normally functions to promote error-free translesion synthesis (TLS) mediated by DNA polymerase eta (Polη). Without H2Bub1, DNA polymerase zeta (Polζ) is responsible for a highly mutagenic alternative mechanism. While H2Bub1 does not appear to regulate other DDT pathways, error-free DDT mechanisms are employed by H2Bub1-deficient cells as another means for survival. However, in these instances, the anti-recombinase, Srs2, is essential to prevent the accumulation of toxic HR intermediates that arise in an unconstrained chromatin environment.