Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal

Du, Li; Li, Yijia; Fakih, Marwan; Wiatrek, Rebecca; Duldulao, Marjun P.; Chen, Zhenbin; Chu, Peiguo; Garcia‐Aguilar, Julio; Chen, Yuan

doi:10.1038/ncomms12326

Cited by 91 publications

(81 citation statements)

References 53 publications

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“…Another member of class IV of TRIM proteins, TRIM21 , also uses the ubiquitin‐ligase activity to regulate stem cell properties, but it is a negative regulator of self‐renewal. As recently reported by Du et al, TRIM21 enhances Oct‐1 ubiquitination and, consequently, reduces Oct‐1 stability, leading to a loss of self‐renewal of colorectal CSCs.…”

Section: The Engagement Of Specific Trims In Stem Cell Maintenancementioning

confidence: 56%

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

et al. 2019

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The tripartite-motif (TRIM) family of proteins represents one of the largest classes of putative single protein RING-finger E3 ubiquitin ligases. The members of this family are characterized by an N-terminal TRIM motif containing one RING-finger domain, one or two zinc-finger domains called B boxes (B1 box and B2 box), and a coiled-coil region.The TRIM motif can be found in isolation or in combination with a variety of C-terminal domains, and based on C-terminus, TRIM proteins are classified into 11 distinct groups.Because of the complex nature of TRIM proteins, they are implicated in a variety of cellular functions and biological processes, including regulation of cell proliferation, cell division and developmental processes, cancer transformation, regulation of cell metabolism, autophagocytosis, modification of chromatin status, regulation of gene transcription, post-translational modifications, and interactions with pathogens. Here, we demonstrate the specific activities of TRIM family proteins that contribute to the cancer stem cell phenotype. A growing body of evidence demonstrates that several TRIM members guarantee the acquisition of stem cell properties and the ability to sustain stem-like phenotype by cancer cells using distinct mechanisms. For other members, further work is needed to understand their full contribution to stem cell self-renewal.Identification of TRIM proteins that possess the potential to serve as therapeutic targets may result in the development of new therapeutic strategies. Finally, these strategies may result in the disruption of the machinery of stemness acquisition, which may prevent tumor growth, progression, and overcome the resistance to anticancer therapies. K E Y W O R D Scancer, pluripotency, RING, self-renewal, stem cells, TRIM

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Section: The Engagement Of Specific Trims In Stem Cell Maintenancementioning

confidence: 56%

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

et al. 2019

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“…The defining feature of CSCs is self-renewal, which is responsible for cancer recurrence and metastasis [16, 29]. To examine the self-renewal properties of each subpopulation, we performed sphere-forming assays.…”

Section: Resultsmentioning

confidence: 99%

“…CSCs are a subset of cells with indefinite passaging ability; they can continuously proliferate and differentiate [2, 29]. Therefore, CSCs have been identified as key factors in cancer growth and metastasis [56].…”

Section: Discussionmentioning

confidence: 99%

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

Leng

Xia

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer. Methods: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR. Results: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations. Conclusion: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.

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“…Loss of SUMO conjugation delays tumor progression in cellular model systems and xenograft models (98). Concordantly, E1 downregulation was recently shown to inhibit colorectal cancer stem cell maintenance and self-renewal (21). Therefore, approaches to target the SUMO system, particularly by interfering in a dose-dependent manner not only with the E1 but also the E2 enzymatic activities, are increasingly discussed and already in experimental phases (21,22,99,100).…”

Section: E1 Regulationmentioning

confidence: 99%

“…These significant rearrangements in the SUMO proteome appear to represent a versatile immediate stress response, required, for example, for DNA damage repair (2,7,18) or to protect the brain against focal cerebral ischemic damage (19). However, constitutively increased sumoylation has rather negative effects and correlates with resistance to cancer treatments, increased tumor metastasis and relapse (20)(21)(22)(23)(24). Also, several other diseases, like neurological disorders, diabetes and heart failure, were connected to defects in the SUMO system (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

SUMO conjugation – a mechanistic view

Pichler

Fatouros

Lee

et al. 2017

Biomolecular Concepts

219

223

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Abstract:The regulation of protein fate by modification with the small ubiquitin-related modifier (SUMO) plays an essential and crucial role in most cellular pathways. Sumoylation is highly dynamic due to the opposing activities of SUMO conjugation and SUMO deconjugation. SUMO conjugation is performed by the hierarchical action of E1, E2 and E3 enzymes, while its deconjugation involves SUMO-specific proteases. In this review, we summarize and compare the mechanistic principles of how SUMO gets conjugated to its substrate. We focus on the interplay of the E1, E2 and E3 enzymes and discuss how specificity could be achieved given the limited number of conjugating enzymes and the thousands of substrates.

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Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal

Cited by 91 publications

References 53 publications

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

SUMO conjugation – a mechanistic view

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