Stabilization of LSD1 by deubiquitinating enzyme USP7 promotes glioblastoma cell tumorigenesis and metastasis through suppression of the p53 signaling pathway

Yi,Lei; Cui,Yan; Xu,Qingfu; Jiang,Yugang

doi:10.3892/or.2016.5099

Stabilization of LSD1 by deubiquitinating enzyme USP7 promotes glioblastoma cell tumorigenesis and metastasis through suppression of the p53 signaling pathway

Authors:
- Lei Yi
- Yan Cui
- Qingfu Xu
- Yugang Jiang
View Affiliations

Affiliations: Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
Published online on: September 16, 2016 https://doi.org/10.3892/or.2016.5099
Pages: 2935-2945

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The substrates and mechanisms of ubiquitin specific peptidase 7 (USP7) in glioma remain unclear. Lysine‑specific demethylase 1 (LSD1) may undergo proteasomal degradation; however, a reciprocal mechanism that stabilizes LSD1 in glioma has not been dertermined. Here co-immunoprecipitation and GST pull-down assays revealed that LSD1 is associated with USP7 in vivo and in vitro. USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells. MTT, EdU proliferation, flow cytometry and Transwell assays indicated that LSD1 played a critical role in the proliferation and invasion of glioblastoma (GBM) cells. We defined the mechanism of USP7 in GBM, through counterbalanced LSD1 ubiquitylation. USP7 caused G0/G1 arrest, promoted tumorigenesis and invasion of A172 and T98G cells. We also uncovered the suppression of the p53 signaling pathway that mediated the activity of USP7 and LSD1. Furthermore, USP7 and LSD1 expression levels were higher in the 150 glioma patients than these levels in normal brain tissues and were correlated with glioma progression. LSD1 was increased concurrently with USP7 during glioblastoma progression and both were predictors for worsened prognosis. Collectively, our study suggested that USP7-LSD1 affects GBM cell proliferation and invasion and may be valuable as novel therapeutic targets and prognostic tools for GBM.

View Figures

View References

1	Lan F, Nottke AC and Shi Y: Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol. 20:316–325. 2008. View Article : Google Scholar : PubMed/NCBI
2	Prusevich P, Kalin JH, Ming SA, Basso M, Givens J, Li X, Hu J, Taylor MS, Cieniewicz AM, Hsiao PY, et al: A selective phenelzine analogue inhibitor of histone demethylase LSD1. ACS Chem Biol. 9:1284–1293. 2014. View Article : Google Scholar : PubMed/NCBI
3	Amente S, Milazzo G, Sorrentino MC, Ambrosio S, Di Palo G, Lania L, Perini G and Majello B: Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma. Oncotarget. 6:14572–14583. 2015. View Article : Google Scholar : PubMed/NCBI
4	Lv T, Yuan D, Miao X, Lv Y, Zhan P, Shen X and Song Y: Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One. 7:e350652012. View Article : Google Scholar : PubMed/NCBI
5	Huang Z, Li S, Song W, Li X, Li Q, Zhang Z, Han Y, Zhang X, Miao S, Du R, et al: Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/β-catenin pathway by down-regulating Dickkopf-1 (DKK1) [corrected]. PLoS One. 8:e700772013. View Article : Google Scholar
6	Ketscher A, Jilg CA, Willmann D, Hummel B, Imhof A, Rüsseler V, Hölz S, Metzger E, Müller JM and Schüle R: LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6. Oncogenesis. 3:e1202014. View Article : Google Scholar : PubMed/NCBI
7	Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L, et al: LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell. 138:660–672. 2009. View Article : Google Scholar : PubMed/NCBI
8	Si W, Huang W, Zheng Y, Yang Y, Liu X, Shan L, Zhou X, Wang Y, Su D, Gao J, et al: Dysfunction of the reciprocal feedback loop between GATA3- and zEB2-nucleated repression programs contributes to breast cancer metastasis. Cancer Cell. 27:822–836. 2015. View Article : Google Scholar : PubMed/NCBI
9	Singh MM, Manton CA, Bhat KP, Tsai WW, Aldape K, Barton MC and Chandra J: Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro Oncol. 13:894–903. 2011. View Article : Google Scholar : PubMed/NCBI
10	Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J and Gu W: Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature. 416:648–653. 2002. View Article : Google Scholar : PubMed/NCBI
11	Brooks CL, Li M, Hu M, Shi Y and Gu W: The p53-Mdm2-HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene. 26:7262–7266. 2007. View Article : Google Scholar : PubMed/NCBI
12	Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T, Zhang RG, Liao J, Lee W, Edwards AM, et al: Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell. 18:25–36. 2005. View Article : Google Scholar : PubMed/NCBI
13	Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J and Pandolfi PP: The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature. 455:813–817. 2008. View Article : Google Scholar : PubMed/NCBI
14	Maertens GN, El Messaoudi-Aubert S, Elderkin S, Hiom K and Peters G: Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor. EMBO J. 29:2553–2565. 2010. View Article : Google Scholar : PubMed/NCBI
15	van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM and Burgering BM: FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol. 8:1064–1073. 2006. View Article : Google Scholar : PubMed/NCBI
16	Huang Z, Wu Q, Guryanova OA, Cheng L, Shou W, Rich JN and Bao S: Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells. Nat Cell Biol. 13:142–152. 2011. View Article : Google Scholar : PubMed/NCBI
17	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
18	Erpolat OP, Akmansu M, Goksel F, Bora H, Yaman E and Büyükberber S: Outcome of newly diagnosed glioblastoma patients treated by radiotherapy plus concomitant and adjuvant temozolomide: A long-term analysis. Tumori. 95:191–197. 2009.PubMed/NCBI
19	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
20	Han X, Gui B, Xiong C, Zhao L, Liang J, Sun L, Yang X, Yu W, Si W, Yan R, et al: Destabilizing LSD1 by Jade-2 promotes neurogenesis: An antibraking system in neural development. Mol Cell. 55:482–494. 2014. View Article : Google Scholar : PubMed/NCBI
21	Cheng C, Niu C, Yang Y, Wang Y and Lu M: Expression of HAUSP in gliomas correlates with disease progression and survival of patients. Oncol Rep. 29:1730–1736. 2013.PubMed/NCBI
22	Periz G, Lu J, Zhang T, Kankel MW, Jablonski AM, Kalb R, McCampbell A and Wang J: Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription. PLoS Biol. 13:e10021142015. View Article : Google Scholar : PubMed/NCBI