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Cancer Cell International
Published in: Cancer Cell International 1/2020

01-12-2020 | Gastric Cancer | Primary research

Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner

Authors: ChitChoon Lim, Jia-Cheng Xu, Tian-Yin Chen, Jia-Xin Xu, Wei-Feng Chen, Jian-Wei Hu, Quan-Lin Li, Yi-Qun Zhang

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

Aberrant expression of ubiquitin-specific peptide 22 (USP22) has been detected in various cancers. This study aimed to investigate the role of USP22 and the underlying mechanism in human gastric cancer.

Methods

The expression pattern of USP22 in human gastric cancer was detected in a tissue microarray containing 88 pairs of gastric cancer tissue and adjacent normal tissue samples from patients with primary gastric cancer using immunohistochemical staining. The correlation of USP22 expression with clinical characteristics of patients, as well as their prognostic values in the overall survival of patients, were evaluated. USP22-overexpressing SGC7901 and USP22-silencing AGS cells were used to explore the role of USP22 in gastric cancer cell behavior in vitro and in vivo. Chromatin immunoprecipitation was performed to identify differentially expressed genes induced by USP22 overexpression. Western blot analysis was conducted to detect the activation of RAS/ERK and PI3K/AKT signaling in USP22-overexpressing SGC7901 cells and xenograft tumor tissues. Knockdown of RAS activator son of sevenless 1 (SOS1) was performed to investigate the role of SOS1 in USP22-regulated gastric cancer cell behavior and RAS signaling both in vitro and in vivo.

Results

USP22 protein expression was significantly increased in human gastric cancer tissues, compared with adjacent normal tissues, and was positively correlated with local tumor stage. Gain- and loss-of-function assays showed that USP22 promoted gastric cancer cell growth and cell cycle transition while suppressing apoptosis in vitro. Consistent results were observed in a xenograft mouse model. Chromatin immunoprecipitation revealed that the overexpression of USP22 induced the upregulation of RAS activator son of sevenless 1 (SOS1) in SGC7901 cells. Western blot analysis showed that USP22 overexpression also induced activation of the RAS/ERK and PI3K/AKT pathways in SGC7901 cells and xenograft tumor tissues. Furthermore, SOS1 silencing could reverse the effects of USP22 on gastric cancer cell behavior and RAS signaling both in vitro and in vivo.

Conclusions

Our results suggest that USP22 acts as an oncogene in gastric cancer in a SOS1-dependent manner, identifying the USP22/SOS1/RAS axis as a potential therapeutic target in gastric cancer.
Appendix
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Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.CrossRef
2.
Yang L, Zheng R, Wang N, Yuan Y, Liu S, Li H, et al. Incidence and mortality of stomach cancer in China, 2014. Chin J Cancer Res. 2018;30:291–8.CrossRef
3.
Zhang XY, Varthi M, Sykes SM, Phillips C, Warzecha C, Zhu W, et al. The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Mol Cell. 2008;29:102–11.CrossRef
4.
Armour SM, Bennett EJ, Braun CR, Zhang XY, McMahon SB, Gygi SP, et al. A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Mol Cell Biol. 2013;33:1487–502.CrossRef
5.
Schrecengost RS, Dean JL, Goodwin JF, Schiewer MJ, Urban MW, Stanek TJ, et al. USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Res. 2014;74:272–86.CrossRef
6.
Yang DD, Cui BB, Sun LY, Zheng HQ, Huang Q, Tong JX, et al. The co-expression of USP22 and BMI-1 may promote cancer progression and predict therapy failure in gastric carcinoma. Cell Biochem Biophys. 2011;61:703–10.CrossRef
7.
Xiong J, Xu X, Zhou X, Liu J, Gong Z, Wu P, et al. USP22 transcriptional activity is negatively regulated by the histone deacetylase inhibitor trichostatin A. Mol Med Rep. 2014;10:3343–7.CrossRef
8.
Ning Z, Wang A, Liang J, Xie Y, Liu J, Feng L, et al. USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via beta-catenin nuclear localization and is associated with poor prognosis in stage II pancreatic ductal adenocarcinoma. Int J Oncol. 2014;45:1594–608.CrossRef
9.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.CrossRef
10.
11.
Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129:1287–92.CrossRef
12.
Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10:842–57.CrossRef
13.
Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15:771–85.CrossRef
14.
Wong GS, Zhou J, Liu JB, Wu Z, Xu X, Li T, et al. Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med. 2018;24:968–77.CrossRef
15.
Castellano E, Downward J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer. 2011;2:261–74.CrossRef
16.
Lam EK, Wang X, Shin VY, Zhang S, Morrison H, Sun J, et al. A microRNA contribution to aberrant Ras activation in gastric cancer. Am J Transl Res. 2011;3:209–18.PubMedPubMedCentral
17.
Keates S, Sougioultzis S, Keates AC, Zhao D, Peek RM Jr, Shaw LM, et al. cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem. 2001;276:48127–34.CrossRef
18.
Matsuoka T, Yashiro M. The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers. 2014;6:1441–63.CrossRef
19.
Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295–308.CrossRef
20.
Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci USA. 2019;116:2551–60.CrossRef
21.
Liu YL, Yang YM, Xu H, Dong XS. Increased expression of ubiquitin-specific protease 22 can promote cancer progression and predict therapy failure in human colorectal cancer. J Gastroenterol Hepatol. 2010;25:1800–5.CrossRef
22.
Wang Z, Zhu L, Guo T, Wang Y, Yang J. Decreased H2B monoubiquitination and overexpression of ubiquitin-specific protease enzyme 22 in malignant colon carcinoma. Hum Pathol. 2015;46:1006–14.CrossRef
23.
Liu YL, Yang YM, Xu H, Dong XS. Aberrant expression of USP22 is associated with liver metastasis and poor prognosis of colorectal cancer. J Surg Oncol. 2011;103:283–9.CrossRef
24.
He Y, Jin YJ, Zhang YH, Meng HX, Zhao BS, Jiang Y, et al. Ubiquitin-specific peptidase 22 overexpression may promote cancer progression and poor prognosis in human gastric carcinoma. Transl Res. 2015;165:407–16.CrossRef
25.
Liu H, Liu N, Zhao Y, Zhu X, Wang C, Liu Q, et al. Oncogenic USP22 supports gastric cancer growth and metastasis by activating c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling. Aging. 2019;11:9643.CrossRef
26.
Yang X, Zang H, Luo Y, Wu J, Fang Z, Zhu W, et al. High expression of USP22 predicts poor prognosis and advanced clinicopathological features in solid tumors: a meta-analysis. Onco Targets Ther. 2018;11:3035–46.CrossRef
27.
Liang J, Zhang XL, Li S, Xie S, Wang WF, Yu RT. Ubiquitin-specific protease 22 promotes the proliferation, migration and invasion of glioma cells. Cancer Biomark. 2018;23:381–9.CrossRef
28.
Zhang H, Han B, Lu H, Zhao Y, Chen X, Meng Q, et al. USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma. Cancer Lett. 2018;433:186–98.CrossRef
29.
Zhao HD, Tang HL, Liu NN, Zhao YL, Liu QQ, Zhu XS, et al. Targeting ubiquitin-specific protease 22 suppresses growth and metastasis of anaplastic thyroid carcinoma. Oncotarget. 2016;7:31191–203.PubMedPubMedCentral
30.
Liu YL, Jiang SX, Yang YM, Xu H, Liu JL, Wang XS. USP22 acts as an oncogene by the activation of BMI-1-mediated INK4a/ARF pathway and Akt pathway. Cell Biochem Biophys. 2012;62:229–35.CrossRef
31.
Ma Y, Fu HL, Wang Z, Huang H, Ni J, Song J, et al. USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein. Oncotarget. 2017;8:33329–42.PubMedPubMedCentral
32.
Wierstra I, Alves J. FOXM1, a typical proliferation-associated transcription factor. Biol Chem. 2007;388:1257–74.PubMed
33.
Lin Z, Tan C, Qiu Q, Kong S, Yang H, Zhao F, et al. Ubiquitin-specific protease 22 is a deubiquitinase of CCNB1. Cell Discov. 2015;1:1–6.CrossRef
34.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22.CrossRef
35.
Zhang L, Hou Y, Ashktorab H, Gao L, Xu Y, Wu K, et al. The impact of C-MYC gene expression on gastric cancer cell. Mol Cell Biochem. 2010;344:125–35.CrossRef
36.
Marampon F, Ciccarelli C, Zani BM. Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors. Mol Cancer. 2006;5:31.CrossRef
37.
Sakamaki J, Daitoku H, Ueno K, Hagiwara A, Yamagata K, Fukamizu A. Arginine methylation of BCL-2 antagonist of cell death (BAD) counteracts its phosphorylation and inactivation by Akt. Proc Natl Acad Sci USA. 2011;108:6085–90.CrossRef
38.
Brock EJ, Ji K, Reiners JJ, Mattingly RR. How to target activated Ras proteins: direct inhibition vs. induced mislocalization. Mini Rev Med Chem. 2016;16:358–69.CrossRef
Metadata
Title
Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner
Authors
ChitChoon Lim
Jia-Cheng Xu
Tian-Yin Chen
Jia-Xin Xu
Wei-Feng Chen
Jian-Wei Hu
Quan-Lin Li
Yi-Qun Zhang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-1137-y

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