Dataset Information

Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.

ABSTRACT: The Lethal giant larvae (Lgl) gene encodes a cortical cytoskeleton protein, Lgl, and is involved in maintaining cell polarity and epithelial integrity. Previously, we observed that Mgl-1, a mammalian homologue of the Drosophila tumor suppressor protein Lgl, is subjected to degradation via ubiquitin-proteasome pathway, and scaffolding protein RanBPM prevents the turnover of the Mgl-1 protein. Consequently, overexpression of RanBPM enhances Mgl-1-mediated cell proliferation and migration. Here, we analyzed the ability of ubiquitin-specific protease 11 (USP11) as a novel regulator of Mgl-1 and it requires RanBPM to regulate proteasomal degradation of Mgl-1. USP11 showed deubiquitinating activity and stabilized Mgl-1 protein. However, USP11-mediated Mgl-1 stabilization was inhibited in RanBPM-knockdown cells. Furthermore, in the cancer cell migration, the regulation of Mgl-1 by USP11 required RanBPM expression. In addition, an in vivo study revealed that depletion of USP11 leads to tumor formation. Taken together, the results indicated that USP11 functions as a tumor suppressor through the regulation of Mgl-1 protein degradation via RanBPM.

SUBMITTER: Lim KH

PROVIDER: S-EPMC4924727 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.

Lim Key-Hwan KH Suresh Bharathi B Park Jung-Hyun JH Kim Young-Soo YS Ramakrishna Suresh S Baek Kwang-Hyun KH

Oncotarget 20160301 12

The Lethal giant larvae (Lgl) gene encodes a cortical cytoskeleton protein, Lgl, and is involved in maintaining cell polarity and epithelial integrity. Previously, we observed that Mgl-1, a mammalian homologue of the Drosophila tumor suppressor protein Lgl, is subjected to degradation via ubiquitin-proteasome pathway, and scaffolding protein RanBPM prevents the turnover of the Mgl-1 protein. Consequently, overexpression of RanBPM enhances Mgl-1-mediated cell proliferation and migration. Here, we ...[more]

PMID: 26919101

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Project description:Ewing sarcoma is the second most common pediatric bone cancer, with a 5-year survival rate for metastatic disease of only 20%. Recent work indicates that survival is strongly correlated with high levels of tumor-infiltrating lymphocytes (TIL), whose abundance is associated with IFN-inducible chemokines CXCL10 and CCL5. However, the tumor-intrinsic factors that drive chemokine production and TIL recruitment have not been fully elucidated. We previously showed that ubiquitin-specific protease 6 (USP6) directly deubiquitinates and stabilizes Jak1, thereby inducing an IFN signature in Ewing sarcoma cells. Here, we show that this gene set comprises chemokines associated with immunostimulatory, antitumorigenic functions, including CXCL10 and CCL5. USP6 synergistically enhanced chemokine production in response to exogenous IFN by inducing surface upregulation of IFNAR1 and IFNGR1. USP6-expressing Ewing sarcoma cells stimulated migration of primary human monocytes and T lymphocytes and triggered activation of natural killer (NK) cells in vitro. USP6 inhibited Ewing sarcoma xenograft growth in nude but not NSG mice and was accompanied by increased intratumoral chemokine production and infiltration and activation of NK cells, dendritic cells, and macrophages, consistent with a requirement for innate immune cells in mediating the antitumorigenic effects of USP6. High USP6 expression in patients with Ewing sarcoma was associated with chemokine production, immune infiltration, and improved survival. This work reveals a previously unrecognized tumor-suppressive function for USP6, which engenders an immunostimulatory microenvironment through pleiotropic effects on multiple immune lineages. This further raises the possibility that USP6 activity may be harnessed to create a "hot" tumor microenvironment in immunotherapy. SIGNIFICANCE: This study reveals a novel tumor-suppressive function for USP6 by inducing an immunostimulatory microenvironment, suggesting that USP6 activity may be exploited to enhance immunotherapy regimens.

Dataset Information

Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.

Publications

Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth.

Similar Datasets

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