The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

McFarlane, Cheryl; Kelvin, Alyson A.; Vega, Michelle de la; Govender, Ureshnie; Scott, Christopher J.; Burrows, James F.; Johnston, James A.

doi:10.1158/0008-5472.can-09-4152

Cited by 85 publications

(101 citation statements)

References 49 publications

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“…These findings provide support for the hypothesis that Dub3 might be a positive regulator of both cell proliferation and survival, which might partly through stabilization of Cdc25A. Similar to our observations, previous shRNA studies have also indicated that Dub3 knockdown reduces proliferation by inhibiting the G1-S phase cell cycle progression and inhibits chemotaxis [14,15,26].…”

Section: Discussionsupporting

confidence: 91%

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Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer

Zhou

Shu

et al. 2015

Biomedicine & Pharmacotherapy

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Section: Discussionsupporting

confidence: 91%

“…found that Dub3-knockdown could significantly impair G1-S transition and block proliferation of tumor-derived cell lines by attenuating GTPase signalling [14]. However, the specific substrates of Dub3 have also been unclear.…”

Section: Introductionmentioning

confidence: 99%

Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer

Zhou

Shu

et al. 2015

Biomedicine & Pharmacotherapy

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“…USP17 reduces the rate of cell proliferation and regulates cell growth and survival (7)(8)(9)(10). We reported that USP17 having two HABMs on its C terminus regulates cell viability and induces apoptosis in adenocarcinoma cells (11).…”

Section: Discussionmentioning

confidence: 99%

“…Recent characterization of USP17 as a key regulator of cell proliferation has revealed its critical role in cell growth and survival (7)(8)(9)(10). Previously, we showed that USP17 possesses two hyaluronan binding motifs (HABMs) in its C-terminal region and interacts with hyaluronan to regulate cell viability (11).…”

mentioning

confidence: 99%

Lys-63-specific Deubiquitination of SDS3 by USP17 Regulates HDAC Activity

Ramakrishna

Suresh

Lee

et al. 2011

Journal of Biological Chemistry

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SDS3 is a key component of the histone deacetylase (HDAC)-dependent Sin3A co-repressor complex, serving to maintain its HDAC activity. Here, we report both exogenous and endogenous functional interaction between deubiquitinating enzyme USP17 and human SDS3 by MALDI-TOF-MS, co-immunoprecipitation assay, and GST pull-down assay. In this study, we demonstrated that SDS3 readily undergoes endogenous polyubiquitination, which is associated specifically with Lys-63-branched polyubiquitin chains and not with Lys-48-branched polyubiquitin chains. Further, we also demonstrated that USP17 specifically deubiquitinates Lys-63-linked ubiquitin chains from SDS3 and regulates its biological functions. The deubiquitinating activity of USP17 on SDS3 negatively regulates SDS3-associated HDAC activity. The constitutive expression of USP17 and its substrate SDS3 was involved in the inhibition of anchorage-independent tumor growth and blocks cell proliferation, leading to apoptosis in cervical carcinoma cells. Furthermore, we showed that USP17 and SDS3 mutually interact with each other to regulate cancer cell viability. These data support the possibility that SDS3, being a substrate of USP17, may play an important role in developing a novel therapeutic means to inhibit specific HDAC activities in cancer.Molecular processes such as phosphorylation, dephosphorylation, acetylation, deacetylation, ubiquitination, and deubiquitination of cellular proteins play an orchestrated role in coordinating homeostasis and contribute to the manifestation of physiological processes in health and disease. The process of ubiquitination is a well established event involving a complex of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligase (E3) enzymes (1-4). Ubiquitination can be reversed by deubiquitinating enzymes (DUBs) 2 (3, 5). Most DUBs are cysteine proteases and consist of at least five known families: the ubiquitin C-terminal hydrolases, the ubiquitin-specific processing proteases (USP), Jab1/ Pab1/MPN domain-containing metallo-enzymes, Otu-domain ubiquitin aldehyde-binding proteins, and Ataxin-3/Josephin (3, 4, 6).USP17 was previously identified as a human ortholog of DUB-3 that is regulated by the IL-4 and IL-6 cytokines (7). Recent characterization of USP17 as a key regulator of cell proliferation has revealed its critical role in cell growth and survival (7-10). Previously, we showed that USP17 possesses two hyaluronan binding motifs (HABMs) in its C-terminal region and interacts with hyaluronan to regulate cell viability (11). However, the biological significance of these HABMs in USP17 remains to be fully understood.The Sin3 co-repressor complex has been linked to HDAC enzymatic activity by directly interacting with HDAC1 and HDAC2 within the Sin3-HDAC complex (12, 13). SDS3 is a subunit of the HDAC-dependent Sin3A co-repressor complex and exhibits a critical role in maintenance of mSin3-associated HDAC activity (14,15). It has a role in transcriptional repression, recruits HDAC activity, and enables...

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“…This gene is overexpressed in several types of human cancer (Gray et al, 1995;Zhang et al, 2011b), and downregulated in small cell lung cancer cell lines (Frederick et al, 1998). Moreover, high levels of USP17 have been identified in primary lung, colon, esophagus and cervix tumor biopsies (McFarlane et al, 2010). Furthermore, USP15 is downregulated in paclitaxelresistant ovarian cancer (Xu et al, 2009), and CYLD in melanoma and other malignant tumors (Hellerbrand et al, 2007;Jenner et al, 2007;Massoumi et al, 2009;Gilbert et al, 2011).…”

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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The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

Cited by 85 publications

References 49 publications

Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer

Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer

Lys-63-specific Deubiquitination of SDS3 by USP17 Regulates HDAC Activity

Deubiquitinases in cancer: new functions and therapeutic options

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