UBE1L causes lung cancer growth suppression by targeting cyclin D1

Feng, Qing; Sekula, David; Guo, Yongli; Liu, Xi; Black, Candice C.; Galimberti, Fabrizio; Shah, Sameena; Sempere, Lorenzo F.; Memoli, Vincent A.; Andersen, Jesper B.; Hassel, Bret A.; Dragnev, Konstantin H.; Dmitrovsky, Ethan

doi:10.1158/1535-7163.mct-08-0753

Cited by 73 publications

(82 citation statements)

References 28 publications

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“…For example, our studies and previous studies have shown that miR-7 has the ability to inhibit several pro-growth signaling proteins including EGFR, IRS-1, IGF-1R, PAK1, and Raf-1 (20,27,45,46). Furthermore, Usp18, and its substrate ISG15, have also been shown to control the stability of pro-growth proteins (49,50). Thus, it is likely that Usp18 activity is regulating cellular growth via a mechanism(s) that is additional to the Usp18/miR-7 pathway regulation of growth promoting proteins.…”

Section: Discussionsupporting

confidence: 54%

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Duex

Comeau

Sorkin

et al. 2011

Journal of Biological Chemistry

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Epidermal growth factor receptor (EGFR) is involved in development and progression of many human cancers. We have previously demonstrated that the ubiquitin-specific peptidase Usp18 (Ubp43) is a potent regulator of EGFR protein expression. Here we report that the 3-untranslated region (3-UTR) of the EGFR message modulates RNA translation following cell treatment with Usp18 siRNA, suggesting microRNA as a possible mediator. Given earlier evidence of EGFR regulation by the microRNA miR-7, we assessed whether miR-7 mediates Usp18 siRNA effects. We found that Usp18 depletion elevates miR-7 levels in several cancer cell lines because of a transcriptional activation and/or mRNA stabilization of miR-7 host genes and that miR-7 acts downstream of Usp18 to regulate EGFR mRNA translation via the 3-UTR. Also, depletion of Usp18 led to a decrease in protein levels of other known oncogenic targets of miR-7, reduced cell proliferation and soft agar colony formation, and increased apoptosis. Notably, all of these phenotypes were reversed by a specific inhibitor of miR-7. Thus, our findings support a model in which Usp18 inhibition promotes upregulation of miR-7, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells.Despite advances in cancer treatments, improvement of overall patient survival remains poor. One of the primary reasons for this low success is the inherent complexity of oncogenic pathways such as those driven by the epidermal growth factor (EGF) 5 receptor (EGFR). EGFR is a member of the receptor tyrosine kinase (RTK) family. Upon binding of ligand, EGFR autophosphorylates at tyrosine residues and triggers an intracellular signal transduction cascade, which ultimately promotes cellular survival and division (1, 2). Dysregulation of EGFR and downstream signaling events is found in a multitude of tumor types (3-6). Therefore, targeting the tyrosine kinase activity of EGFR with small molecule inhibitors or targeting EGFR with antibodies has been a focus in the treatment of several tumors, including brain (glioblastoma), cervical, lung, and head and neck (squamous cell carcinoma). However, this strategy has resulted in minimal success. A major limitation of these approaches is that tumor cells eventually develop resistance to the current therapeutics. The resistance develops through increased ligand expression, additional somatic mutations in the EGFR tyrosine kinase domain, and increased heterodimerization with other RTKs (3, 7-9).As an alternative to developing approaches to directly inhibit EGFR signaling, our recent efforts focused on identifying allosteric modulators of EGFR protein levels. Inhibition of these modulators has the potential to significantly decrease EGFR protein levels irrespective of ligand levels or EGFR mutational status. Using a library of small interfering RNAs (siRNAs) that target deubiquitinase enzymes (DUBs), a class of proteins known to regulate receptor trafficking and expression (10 -12), we identified a number of candidate proteins which regulate EGFR prote...

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Section: Discussionsupporting

confidence: 54%

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Duex

Comeau

Sorkin

et al. 2011

Journal of Biological Chemistry

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“…While there are several potential interpretations of the data, we favor the pattern of gene expression for dampening of proliferation for the following several reasons: (1) genes associated with cell division are relatively low (KIF2C, CDT1, E2F2); (2) certain genes induce a nonproliferative state (TGFBR2) [25] or block internalization of EGFR (RAB11FIP2) [26], which favors motility over proliferation [27,28]; and (3) increased phosphatase expression that can modulate pathway activation (PTPRK) [29]. With increased expression of MAP2K1 and RAF1 and decreased expression of PITX1, ISG15, CEBPA, MKNK2 and SOX2 [30][31][32][33][34], we believe that the phosphatases are particularly interesting because they serve to inactivate kinase cascades [35,36] and can modulate pathway interaction, such as EGF and TGF-beta [29]. In addition, Notch1, which has been recently identified as a tumor suppressor for SCC, is decreased in high cytoplasmic ezrin tumors and may dampen kinase activity [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma

Brandwein-Gensler

Smith

Kawachi

et al. 2012

Head and Neck Pathol

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Members of the 4.1 superfamily of proteins, including ezrin, moesin, merlin, and willin regulate many normal physiologic processes such as cellular shape, motility, and proliferation. In addition, they contribute both to tumor development and tumor progression. We reported previously that strong cytoplasmic ezrin expression was independently associated with poorer patient survival. One hundred and thirty-one histologically confirmed primary head and neck squamous cell carcinomas were examined prospectively for cancer progression and survival at a large health care center in the Bronx, NY, USA. Immunohistochemical analysis of ezrin, moesin, merlin, and willin expression in tissue microarray samples of primary head and neck squamous cell carcinoma revealed a significant association of increased cytoplasmic ezrin with poor cancer survival. Global RNA analyses suggest that cancers with high cytoplasmic ezrin have a more invasive phenotype.This study supports our previous findings associating cytoplasmic ezrin with more aggressive behavior and poorer outcome and indicates the need for a multi-institutional study to validate the use of cytoplasmic ezrin as a biomarker for treatment planning in head and neck squamous cell carcinoma.

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“…C10 cells were cultured in CMRL 1066 medium (Life Technologies) with 10% FBS, 2 mM l-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin (18). BEAS-2B cells were cultured in serum-free LHC-9 medium (Invitrogen), as reported (42).…”

Section: Figurementioning

confidence: 99%

MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors

et al. 2010

Self Cite

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MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice. We found that miR-136, miR-376a, and miR-31 were each prominently overexpressed in murine lung cancers. Real-time RT-PCR and in situ hybridization (ISH) assays confirmed these miRNA expression profiles in paired normalmalignant lung tissues from mice and humans. Engineered knockdown of miR-31, but not other highlighted miRNAs, substantially repressed lung cancer cell growth and tumorigenicity in a dose-dependent manner. Using a bioinformatics approach, we identified miR-31 target mRNAs and independently confirmed them as direct targets in human and mouse lung cancer cell lines. These targets included the tumor-suppressive genes large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A), and expression of each was augmented by miR-31 knockdown. Their engineered repression antagonized miR-31-mediated growth inhibition. Notably, miR-31 and these target mRNAs were inversely expressed in mouse and human lung cancers, underscoring their biologic relevance. The clinical relevance of miR-31 expression was further independently and comprehensively validated using an array containing normal and malignant human lung tissues. Together, these findings revealed that miR-31 acts as an oncogenic miRNA (oncomir) in lung cancer by targeting specific tumor suppressors for repression.

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UBE1L causes lung cancer growth suppression by targeting cyclin D1

Cited by 73 publications

References 28 publications

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma

MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors

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