The Epigenetic Modifier Ubiquitin-specific Protease 22 (USP22) Regulates Embryonic Stem Cell Differentiation via Transcriptional Repression of Sex-determining Region Y-box 2 (SOX2)

Sussman, Robyn T.; Stanek, Timothy J.; Esteso, Paul; Gearhart, John D.; Knudsen, Karen E.; McMahon, Steven B.

doi:10.1074/jbc.m113.469783

Cited by 78 publications

(73 citation statements)

References 75 publications

(75 reference statements)

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“…Such a reduction could be driven by a variety of mechanisms, including RNF20 promoter hypermethylation 14 or increased expression of pertinent DUBs. 9,13,23,24 We previously reported that RNF20 silencing promotes the migration of non-transformed human mammary epithelial MCF10A cells, and facilitates transformation of mouse cells, consistent with a tumor-suppressive role. 14 Moreover, reduced levels of RNF20 and H2Bub1, observed in colitis and colorectal cancer in mice and humans, can increase the expression of cytokines via the NF-κB pathway, promoting chronic inflammation and colitis-associated colorectal cancer.…”

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confidence: 63%

RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

et al. 2017

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Breast cancer subtypes display distinct biological traits that influence their clinical behavior and response to therapy. Recent studies have highlighted the importance of chromatin structure regulators in tumorigenesis. The RNF20-RNF40 E3 ubiquitin ligase complex monoubiquitylates histone H2B to generate H2Bub1, while the deubiquitinase (DUB) USP44 can remove this modification. We found that RNF20 and RNF40 expression and global H2Bub1 are relatively low, and USP44 expression is relatively high, in basal-like breast tumors compared with luminal tumors. Consistent with a tumor-suppressive role, silencing of RNF20 in basal-like breast cancer cells increased their proliferation and migration, and their tumorigenicity and metastatic capacity, partly through upregulation of inflammatory cytokines. In contrast, in luminal breast cancer cells, RNF20 silencing reduced proliferation, migration and tumorigenic and metastatic capacity, and compromised estrogen receptor transcriptional activity, indicating a tumor-promoting role. Notably, the effects of USP44 silencing on proliferation and migration in both cancer subtypes were opposite to those of RNF20 silencing. Hence, RNF20 and H2Bub1 have contrasting roles in distinct breast cancer subtypes, through differential regulation of key transcriptional programs underpinning the distinctive traits of each subtype.

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confidence: 63%

RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

et al. 2017

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“…2,3,25,[48][49][50] However, knowledge regarding the precise mechanisms underlying how Sox2 is posttranslationally regulated remains limited. Several studies have shown that the protein activity of Sox2 can be modified by sumoylation, methylation, acetylation and phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Ube2s regulates Sox2 stability and mouse ES cell maintenance

et al. 2015

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Sox2 has a critical role in embryonic stem (ES) cell maintenance and differentiation. Interestingly, its activity is highly dosagedependent. Although transcriptional regulation of Sox2 has been extensively studied, the mechanisms orchestrating its degradation remain unclear. In this study, we identified ubiquitin-conjugating enzyme E2S (Ube2s) as a novel effector for Sox2 protein degradation. Ube2s mediates K11-linked polyubiquitin chain formation at the Sox2-K123 residue, thus marking it for proteasome-mediated degradation. Besides its role in fine-tuning the precise level of Sox2, Ube2s reinforces the self-renewing and pluripotent state of ES cells. Importantly, it also represses Sox2-mediated ES cell differentiation toward the neural ectodermal lineage.

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“…In addition, USP22 deubiquitinates intracellular protein, including the shelterin protein telomeric repeat binding factor 1 (4), the histone deacetylase sirtuin 1 (5) and the far upstream element-binding protein 1 fructose-1,6-bisphosphatase 1 (4), and therefore performs an extensive physiological function. A murine study showed that USP22 also regulates embryonic stem cell differentiation (6). In humans, the USP22 gene is located on chromosome 17, consists of 14 exons, and is transcribed and produced broadly across various tissues (7).…”

Section: Introductionmentioning

confidence: 99%

p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells

et al. 2015

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Abstract. Elevated expression of ubiquitin-specific processing enzyme 22 (USP22) was identified in multiple types of human cancers, and was correlated with tumorigenesis and progression. Despite an increase in the numbers of studies in the physiological function of USP22, little is known regarding the regulation of its expression. The 5' flanking sequence of the USP22 gene was recently characterized. In the present study, USP22 transcription was regulated by p38 mitogen-activated protein kinase (MAPK). Treatment of human cervical carcinoma (HeLa) cells with SB203580, an inhibitor of p38 MAPK, enhanced basal USP22 promoter activity and mRNA abundance. Transfection of MAPK kinase 6 (MKK6), an upstream activator of p38 MAPK, resulted in a 40% decrease in USP22 mRNA, while the dominant negative MKK6 increased the transcription level of the USP22, similar to SB203580. Dual luciferase report assays showed that mutations of the Sp1 binding site ahead of the transcription start site abolished the promoting effect of the USP22 promoter by SB203580. Cisplatin, the activator of p38 MAPK, also suppressed USP22 expression. This suppression was blocked by SB203580. In conclusion, p38 MAPK acts as an upstream negative regulator of USP22 transcription in HeLa cells. IntroductionUbiquitin-specific processing enzyme 22 (USP22) is a novel deubiquitinating enzyme that can cleave ubiquitin (Ub) from Ub-conjugated protein substrates (1). As the subunit of the human SAGA coactivator complex, USP22 is linked to the regulation of gene transcription by deubiquitinating histones H2A and H2B (2,3). In addition, USP22 deubiquitinates intracellular protein, including the shelterin protein telomeric repeat binding factor 1 (4), the histone deacetylase sirtuin 1 (5) and the far upstream element-binding protein 1 fructose-1,6-bisphosphatase 1 (4), and therefore performs an extensive physiological function. A murine study showed that USP22 also regulates embryonic stem cell differentiation (6). In humans, the USP22 gene is located on chromosome 17, consists of 14 exons, and is transcribed and produced broadly across various tissues (7). Of note, elevated levels of USP22 have been identified in numerous types of human cancer, including colorectal (8) lung (9) and breast cancer (10). USP22 has been indicated in tumorigenesis. Deletion of USP22 leads to the accumulation of cells in the G 1 phase of the cell cycle (2). For these reasons, USP22 is a putative cancer stem cell marker. Reducing the rate of USP22 expression may be a suitable target for cancer therapy (11). However, the mechanisms that lead to USP22 transcriptional activation, particularly in the human tumor cells, remain unknown.Previously, USP22 transcription was activated by mitogen stimulation or viral infection in normal T and B lymphocytes (12), suggesting the regulation of USP22 gene expression occurs mainly at the transcriptional level. However, the mechanism in which signal transduction pathways regulate USP22 transcription is unclear. It is well-known that activation of the mito...

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The Epigenetic Modifier Ubiquitin-specific Protease 22 (USP22) Regulates Embryonic Stem Cell Differentiation via Transcriptional Repression of Sex-determining Region Y-box 2 (SOX2)

Cited by 78 publications

References 75 publications

RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

Ube2s regulates Sox2 stability and mouse ES cell maintenance

p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells

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