TRIM28 and Interacting KRAB-ZNFs Control Self-Renewal of Human Pluripotent Stem Cells through Epigenetic Repression of Pro-differentiation Genes

Oleksiewicz, Urszula; Gladych, Marta; Raman, Ayush T.; Heyn, Holger; Mereu, Elisabetta; Chlebanowska, Paula; Andrzejewska, Anastazja; Sozańska, Barbara; Samant, Neha S.; Fąk, Katarzyna; Auguścik, Paulina; Kosiński, Marcin; Wróblewska, Joanna; Tomczak, Katarzyna; Kulcenty, Katarzyna; Płoski, Rafał; Biecek, Przemysław; Esteller, Manel; Shah, Parantu K.; Rai, Kunal; Wiznerowicz, Maciej

doi:10.1016/j.stemcr.2017.10.031

Cited by 65 publications

(69 citation statements)

References 41 publications

(66 reference statements)

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“…All members of the sixth class of TRIM proteins (TRIM24, TRIM28, and TRIM33) that possess C‐terminal PHD and BROMO domains are engaged in the stemness regulation at this level (either as activators of pluripotency genes or suppressors of differentiating markers). Besides using the TRIM motif, these proteins engage both PHD and BROMO domains to exert their specific functions . Distinct TRIM members were also shown to participate in epigenetic mechanisms underlying the acquisition or maintenance of CSC phenotype.…”

Section: Molecular Modes Of Trim Actionsmentioning

confidence: 99%

“…43 TRIM28 uses KRAB-ZNFs to cause epigenetic silencing of its target differentiation genes via H3K9me3 and DNA methylation, sustaining the self-renewal of human pluripotent stem cells. 15,16 Additionally, TRIM28 is essential to maintain stem cell properties of cancer cells. Together with MAGE-A3/6, TRIM28 forms a cancer-specific ubiquitinase that regulates the AMPK level in cancer cells, enhancing oxidative phosphorylation and maintaining stem cell traits.…”

Section: Trim Family Members With C-terminal Phd and Bromo Domainsmentioning

confidence: 99%

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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: Molecular Modes Of Trim Actionsmentioning

confidence: 99%

Section: Trim Family Members With C-terminal Phd and Bromo Domainsmentioning

confidence: 99%

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

et al. 2019

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“…This includes ZNF695 (Juarez‐Mendez et al ., ; Li et al ., , ; Takahashi et al ., ), ZNF320 (Chernova et al ., ), ZNF138 (Tommerup and Vissing, ), ZNF200 (Peedicayil et al ., ), ZNF707 (Nesslinger et al ., ), and ZNF354A (von Eyben, ). Interestingly, cancer‐related upregulation of ZNF695 , ZNF714 , and ZNF138 mirrors the differential expression observed between pluripotent stem cells and differentiated cells (Oleksiewicz et al ., ). This observation underlines the similarities between cancer and stem cell expression profiles.…”

Section: Discussionmentioning

confidence: 97%

“…In LUSC, ZNF695 revealed the highest level in the primitive mRNA subtype with overexpressed proliferation genes (Wilkerson et al, 2010). Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of selfrenewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al, 2017). Its involvement in the stem cell phenotype was particularly evident in breast cancers, in which ZNF695 expression was the most abundant in basal-like tumors, known for their high content of stem cells (Honeth et al, 2008;Park et al, 2010).…”

Section: Discussionmentioning

confidence: 98%

“…Together, these proteins silence transcription by triggering the formation of heterochromatin (Czerwinska et al ., ; Ecco et al ., ; Groner et al ., ). Moreover, we and others have shown that at least in a stem cell context, KRAB‐ZNFs may mediate methylation of the DNA sequences adjacent to their binding motifs (Oleksiewicz et al ., ; Quenneville et al ., ; Wiznerowicz et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

et al. 2019

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The KRAB ‐ ZNF (Krüppel‐associated box domain zinc finger) gene family is composed of a large number of highly homologous genes, gene isoforms, and pseudogenes. The proteins encoded by these genes, whose expression is often tissue‐specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation. Due to its high complexity, the KRAB ‐ ZNF family has not been studied in sufficient detail, and the involvement of its members in carcinogenesis remains mostly unexplored. In this study, we aimed to provide a comprehensive description of cancer‐associated KRAB ‐ ZNF s using publicly available The Cancer Genome Atlas pan‐cancer datasets. We analyzed 6727 tumor and normal tissue samples from 16 cancer types. Here, we showed that a small but distinctive cluster of 16 KRAB ‐ ZNF s is commonly upregulated across multiple cancer cohorts in comparison to normal samples. We confirmed these observations in the independent panels of lung and breast cancer cell lines and tissues. This upregulation was also observed for most of the KRAB ‐ ZNF splicing variants, whose expression is simultaneously upregulated in tumors compared to normal tissues. Finally, by analyzing the clinicopathological data for breast and lung cancers, we demonstrated that the expression of cancer‐associated KRAB ‐ ZNF s correlates with patient survival, tumor histology, and molecular subtyping. Altogether, our study allowed the identification and characterization of KRAB ‐ ZNF factors that may have an essential function in cancer biology and thus potential to become novel oncologic biomarkers and treatment targets.

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The association between bromodomain proteins and cancer stemness in different solid tumor types

Czerwińska

Jaworska

Wlodarczyk

et al. 2022

Intl Journal of Cancer

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Cancer stemness, which covers the stem cell-like molecular traits of cancer cells, is essential for tumor development, progression and relapse. Both transcriptional and epigenetic aberrations are essentially connected with cancer stemness. The engagement of bromodomain (BrD) proteins-a family of epigenetic factors-has been presented in the pathogenesis of several tumor types, although their association with cancer stemness remains largely unknown. Here, we harnessed TCGA and GEO databases and used several bioinformatic tools (ie, Oncomine, PrognoScan, GEPIA2, TIMER2.0, TISIDB, GSEA, R2 platform) to characterize the association between the BrD family members' expression and cancer stemness in solid tumors. Our results demonstrate that significant upregulation of ATAD2 and SMARCA4, and downregulation of SMARCA2 is consistently associated with enriched cancer stem cell-like phenotype, respectively. Especially, higher-grade tumors that display stem cell-like properties overexpress ATAD2. In contrast to most BrD members, the gene expression profiles of ATAD2 HIGH expressing tumors are strongly enriched with known markers of stem cells and with specific targets for c-Myc transcription factor.For other BrD proteins, the association with cancer de-differentiation status is rather tumor-specific. Our results demonstrate for the first time the relation between distinct BrD family proteins and cancer stemness across 27 solid tumor types. Specifically, our approach allowed us to discover a robust association of high ATAD2 expression with cancer stemness and reveal its' versatility in tumors.

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TRIM28 and Interacting KRAB-ZNFs Control Self-Renewal of Human Pluripotent Stem Cells through Epigenetic Repression of Pro-differentiation Genes

Cited by 65 publications

References 41 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

The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

The association between bromodomain proteins and cancer stemness in different solid tumor types

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