USP2 Promotes Cell Proliferation and Metastasis in Choroidal Melanoma Via Stabilizing Snail

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2023 May 18

PMID 37199836

Authors

Chao Wei

Xiaofei Zhao

Han Zhang

Lijuan Wang

Affiliations

Soon will be listed here.

Abstract

Background: Choroidal melanoma (CM) is an intraocular tumor that arises from melanocytes. While ubiquitin-specific protease 2 (USP2) modulates the progression of numerous diseases, its role in CM is not known. This study aimed to determine the role of USP2 in CM and elucidate its molecular mechanisms.

Methods: MTT, Transwell, and wound-scratch assays were used to investigate the function of USP2 in the proliferation and metastasis of CM. Western blotting and qRT-PCR were used to analyze the expression of USP2, Snail, and factors associated with the epithelial-mesenchymal transition (EMT). The relationship between USP2 and Snail was explored by co-immunoprecipitation and in vitro ubiquitination assays. A nude mouse model of CM was established for verifying the role of USP2 in vivo.

Results: USP2 overexpression promoted proliferation and metastasis, and induced the EMT in CM cells in vitro, while specific inhibition of USP2 by ML364 produced the opposite effects. ML364 also suppressed CM tumor growth in vivo. Mechanistically, USP2 is known to deubiquitinate Snail, stabilizing the latter through the removal of its K48 poly-ubiquitin chains. However, a catalytically inactive form of USP2 (C276A) had no effect on Snail ubiquitination and failed to increase Snail protein expression. The C276A mutant was also unable to promote CM cell proliferation, migration, and invasion, as well as EMT progression. Furthermore, Snail overexpression partly counteracted the effects of ML364 on proliferation and migration, while rescuing the effects of the inhibitor on the EMT.

Conclusions: The findings demonstrated that USP2 modulated CM development through the stabilization of Snail and suggest that USP2 may be a useful target for the development of novel treatments for CM.

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References

Asnaghi L, Gezgin G, Tripathy A, Handa J, Merbs S, van der Velden P . EMT-associated factors promote invasive properties of uveal melanoma cells. Mol Vis. 2015; 21:919-29. PMC: 4548792. View

Bagger M, Espensen C, Rasmussen K, Dogrusoz M, Jager M, Appelt A . Genetic Status Affects Disease-Specific Mortality But Not the Incidence of Local Recurrence in Patients with Uveal Melanoma. Ophthalmology. 2023; 130(8):822-829. DOI: 10.1016/j.ophtha.2023.03.010. View

Bustamante P, Piquet L, Landreville S, Burnier J . Uveal melanoma pathobiology: Metastasis to the liver. Semin Cancer Biol. 2020; 71:65-85. DOI: 10.1016/j.semcancer.2020.05.003. View

Chen Y, Lu X, Montoya-Durango D, Liu Y, Dean K, Darling D . ZEB1 Regulates Multiple Oncogenic Components Involved in Uveal Melanoma Progression. Sci Rep. 2017; 7(1):45. PMC: 5428321. DOI: 10.1038/s41598-017-00079-x. View

Dai X, Lu L, Deng S, Meng J, Wan C, Huang J . USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer. Theranostics. 2020; 10(20):9332-9347. PMC: 7415808. DOI: 10.7150/thno.47137. View

Davis M, Pragani R, Fox J, Shen M, Parmar K, Gaudiano E . Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models. J Biol Chem. 2016; 291(47):24628-24640. PMC: 5114414. DOI: 10.1074/jbc.M116.738567. View

Dongre A, Weinberg R . New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2018; 20(2):69-84. DOI: 10.1038/s41580-018-0080-4. View

Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein L . The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell. 2004; 5(3):253-61. DOI: 10.1016/s1535-6108(04)00055-8. View

He J, Lee H, Saha S, Ruan D, Guo H, Chan C . Inhibition of USP2 eliminates cancer stem cells and enhances TNBC responsiveness to chemotherapy. Cell Death Dis. 2019; 10(4):285. PMC: 6437220. DOI: 10.1038/s41419-019-1512-6. View

10.

Herrspiegel C, Kvanta A, Lardner E, Ramskold Cabaca L, Wells J, Bartuma K . Nuclear expression of BAP-1 in transvitreal incisional biopsies and subsequent enucleation of eyes with posterior choroidal melanoma. Br J Ophthalmol. 2020; 105(4):582-586. PMC: 8005798. DOI: 10.1136/bjophthalmol-2020-316498. View

11.

Jin Y, Zhang Y, Li B, Zhang J, Dong Z, Hu X . TRIM21 mediates ubiquitination of Snail and modulates epithelial to mesenchymal transition in breast cancer cells. Int J Biol Macromol. 2018; 124:846-853. DOI: 10.1016/j.ijbiomac.2018.11.269. View

12.

Inden M, Takagi A, Kitai H, Ito T, Kurita H, Honda R . Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro. Int J Mol Sci. 2021; 22(21). PMC: 8584179. DOI: 10.3390/ijms222111484. View

13.

Kosinsky R, Zerche M, Saul D, Wang X, Wohn L, Wegwitz F . USP22 exerts tumor-suppressive functions in colorectal cancer by decreasing mTOR activity. Cell Death Differ. 2019; 27(4):1328-1340. PMC: 7205880. DOI: 10.1038/s41418-019-0420-8. View

14.

Lamouille S, Xu J, Derynck R . Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15(3):178-96. PMC: 4240281. DOI: 10.1038/nrm3758. View

15.

Ling S, Shan Q, Zhan Q, Ye Q, Liu P, Xu S . USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation. Gut. 2019; 69(7):1322-1334. DOI: 10.1136/gutjnl-2019-319616. View

16.

Ma X, Ma X, Qiu Y, Zhu L, Lin Y, You Y . TRIM50 suppressed hepatocarcinoma progression through directly targeting SNAIL for ubiquitous degradation. Cell Death Dis. 2018; 9(6):608. PMC: 5964248. DOI: 10.1038/s41419-018-0644-4. View

17.

Ma A, Tang M, Zhang L, Wang B, Yang Z, Liu Y . USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis. Oncogene. 2018; 38(13):2405-2419. DOI: 10.1038/s41388-018-0590-8. View

18.

Mittal V . Epithelial Mesenchymal Transition in Tumor Metastasis. Annu Rev Pathol. 2018; 13:395-412. DOI: 10.1146/annurev-pathol-020117-043854. View

19.

Jung C, Ihm Y, Cho D, Lee H, Nam D, Kim S . Inducing thermodynamically blocked atomic ordering via strongly driven nonequilibrium kinetics. Sci Adv. 2021; 7(52):eabj8552. PMC: 8694629. DOI: 10.1126/sciadv.abj8552. View

20.

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View