<b>
                     <i>USP6 (Tre2)</i>
                  </b> Fusion Oncogenes in Aneurysmal Bone Cyst

Oliveira, André M.; Hsi, Bae‐Li; Weremowicz, Stanislawa; Rosenberg, Andrew E.; Cin, Paola Dal; Joseph, Nora; Bridge, Julia A.; Perez‐Atayde, Antonio R.; Fletcher, Jonathan A.

doi:10.1158/0008-5472.can-03-2827

Cited by 278 publications

(174 citation statements)

References 15 publications

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“…USP6 translocations are the key etiological agent in two human tumors, ABC and nodular fasciitis (26,27). In both, the USP6 rearrangement leads to overexpression of wild-type USP6 protein in a mesenchymal cell of origin.…”

Section: Discussionmentioning

confidence: 99%

“…USP6 is implicated in human nonmalignant neoplastic disorders, with chromosomal translocationdriven overexpression of USP6 occurring in two independent tumor types, ABC and nodular fasciitis, in ∼70% and 90% of cases, respectively (26,27). To determine if a Wnt/β-catenin gene signature is activated in these tumors, gene expression profiling by microarray analysis was performed on nodular fasciitis tumors with confirmed USP6 translocation/overexpression.…”

Section: Usp6 Functions Upstream Of the Destruction Complex And Requiresmentioning

confidence: 99%

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USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Madan

Walker

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.

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Section: Discussionmentioning

confidence: 99%

Section: Usp6 Functions Upstream Of the Destruction Complex And Requiresmentioning

confidence: 99%

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Madan

Walker

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The lesion most commonly arises in the first two decades of life and is a clonal proliferation associated with a characteristic rearrangement of the short arm of chromosome 17. [3][4][5] Osteoclasts are formed from marrow-derived circulating precursors, which express a monocyte/macrophage phenotype. 6,7 These mononuclear phagocyte precursors express the receptor activator of nuclear factor kB (RANK) and, in the presence of macrophage-colony stimulating factor (M-CSF) and the ligand for RANK (RANKL), differentiate into multinucleated cells that express the specific cytochemical and functional phenotype of mature bone-resorbing osteoclasts.…”

mentioning

confidence: 99%

CD14− mononuclear stromal cells support (CD14+) monocyte–osteoclast differentiation in aneurysmal bone cyst

Taylor

Kashima

Hemingway

et al. 2012

Laboratory Investigation

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Aneurysmal bone cyst (ABC) is a benign osteolytic bone lesion in which there are blood-filled spaces separated by fibrous septa containing giant cells. The nature of the giant cells in this lesion and the mechanism of bone destruction in ABC is not certain. In this study, we have analysed several characteristics of mononuclear and multinucleated cells in the ABC and examined the cellular and molecular mechanisms of ABC osteolysis. The antigenic and functional phenotype of giant cells in ABC was determined by histochemistry/immunohistochemistry using antibodies to macrophage and osteoclast markers. Giant cells and CD14 þ and CD14À mononuclear cells were isolated from ABC specimens and cultured on dentine slices and coverslips with receptor activator of nuclear factor kB ligand (RANKL) þ /À macrophage-colony stimulating factor (M-CSF) and functional and cytochemical evidence of osteoclast differentiation sought. Giant cells in ABC expressed an osteoclast-like phenotype (CD51 þ , CD14À, cathepsin K þ , TRAP þ ) and were capable of lacunar resorption, which was inhibited by zoledronate, calcitonin and osteoprotegerin (OPG). When cultured with RANKL ± M-CSF, CD14 þ , but not CD14À, mononuclear cells differentiated into TRAP þ multinucleated cells that were capable of lacunar resorption. M-CSF was not necessary for osteoclast formation from CD14 þ cell cultures. CD14À cells variably expressed RANKL, OPG and M-CSF but supported osteoclast differentiation. Our findings show that the giant cells in ABC express an osteoclast-like phenotype and are formed from CD14 þ macrophage precursors. CD14À mononuclear stromal cells express osteoclastogenic factors and most likely interact with CD14 þ cells to form osteoclast-like giant cells by a RANKL-dependent mechanism.Laboratory Investigation (2012) 92, 600-605; doi:10.1038/labinvest.2012.5; published online 13 February 2012 KEYWORDS: aneurysmal bone cyst (ABC); bisophosphonate; bone resorption; giant cell; osteoclast Benign and malignant tumours that contain numerous osteoclast-like giant cells frequently arise in bone and are categorised on the basis of tissue location and histomorphology. 1,2 The mechanism whereby giant cells accumulate and contribute to the osteolysis that accompanies growth of these tumours in bone is not certain. Primary aneurysmal bone cyst (ABC) is a benign cystic giant cell-rich tumour that arises most commonly in the metaphyseal region of a long bone; 1,2 the cysts are filled with blood and the fibrous cyst wall contains fibroblast-like stromal cells, scattered macrophages and osteoclast-like giant cells. The lesion most commonly arises in the first two decades of life and is a clonal proliferation associated with a characteristic rearrangement of the short arm of chromosome 17. [3][4][5] Osteoclasts are formed from marrow-derived circulating precursors, which express a monocyte/macrophage phenotype. 6,7 These mononuclear phagocyte precursors express the receptor activator of nuclear factor kB (RANK) and, in the presence of macrophage-colony stimulating...

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“…Regarding DUBs with oncogenic roles, somatic mutations in USP6 and USP28 have been found in different human malignancies. Thus, chromosomal rearrangements that create a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region causes the overexpression of USP6-also known as Tre2-turn this DUB into an oncogene associated with neoplastic aneurismal bone cysts (Oliveira et al, 2004). As for USP28, mutations in this gene have been reported in cases of lobular breast cancer (Shah et al, 2009).…”

Section: Genetic or Functional Alterations Of Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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USP6 (Tre2) Fusion Oncogenes in Aneurysmal Bone Cyst

Cited by 278 publications

References 15 publications

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

CD14− mononuclear stromal cells support (CD14+) monocyte–osteoclast differentiation in aneurysmal bone cyst

Deubiquitinases in cancer: new functions and therapeutic options

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