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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2018

Open Access 01-12-2018 | Research

Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy

Authors: Tong Shen, Ling-Dong Cai, Yu-Hong Liu, Shi Li, Wen-Juan Gan, Xiu-Ming Li, Jing-Ru Wang, Peng-Da Guo, Qun Zhou, Xing-Xing Lu, Li-Na Sun, Jian-Ming Li

Published in: Journal of Hematology & Oncology | Issue 1/2018

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Abstract

Background

Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin–proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC.

Methods

Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression.

Results

Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC.

Conclusions

Our study functionally links Ube2v1, an E2 member in the ubiquitin–proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.
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Literature
1.
Burger AM, Seth AK. The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer. 2004;40:2217–29.CrossRefPubMed
2.
Hershko A, Heller H, Elias S, Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem. 1983;258:8206–14.PubMed
3.
4.
Kraft C, Peter M, Hofmann K. Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol. 2010;12:836–41.CrossRefPubMed
5.
Kirkin V, McEwan DG, Novak I, Dikic I. A role for ubiquitin in selective autophagy. Mol Cell. 2009;34:259–69.CrossRefPubMed
6.
Rogov V, Dotsch V, Johansen T, Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell. 2014;53:167–78.CrossRefPubMed
7.
Lu K, Psakhye I, Jentsch S. A new class of ubiquitin-Atg8 receptors involved in selective autophagy and polyQ protein clearance. Autophagy. 2014;10:2381–2.CrossRefPubMed
8.
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature. 2015;524:361–5.CrossRefPubMedPubMedCentral
9.
10.
11.
Liu Z, Chen P, Gao H, Gu Y, Yang J, Peng H, et al. Ubiquitylation of autophagy receptor Optineurin by HACE1 activates selective autophagy for tumor suppression. Cancer Cell. 2014;26:106–20.CrossRefPubMedPubMedCentral
12.
Sheen JH, Zoncu R, Kim D, Sabatini M. Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell. 2011;19:613–28.CrossRefPubMedPubMedCentral
13.
Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.CrossRefPubMed
14.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10:51–64.CrossRefPubMedPubMedCentral
15.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–75.CrossRefPubMedPubMedCentral
16.
Liu H, He Z, Simon HU. Autophagy suppresses melanoma tumorigenesis by inducing senescence. Autophagy. 2014;10:372–3.CrossRefPubMed
17.
18.
Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015;34:856–80.CrossRefPubMedPubMedCentral
19.
Rothofsky ML, Lin SL. CROC-1 encodes a protein which mediates transcriptional activation of the human FOS promoter. Gene. 1997;195:141–9.CrossRefPubMed
20.
Deng L, Wang C, Spencer E, Yang L, Braun A, You J, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103:351–61.CrossRefPubMed
21.
Thomson TM, Khalid H, Lozano JJ, Sancho E, Arino J. Role of UEV-1A, a homologue of the tumor suppressor protein TSG101, in protection from DNA damage. FEBS Lett. 1998;423:49–52.CrossRefPubMed
22.
Ma L, Broomfield S, Lavery C, Lin SL, Xiao W, Bacchetti S. Up-regulation of CIR1/CROC1 expression upon cell immortalization and in tumor-derived human cell lines. Oncogene. 1998;17:1321–6.CrossRefPubMed
23.
Wu Z, Shen S, Zhang Z, Zhang W, Xiao W. Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-small ka, CyrillicB mediated matrix metalloproteinase-1 gene regulation. Breast Cancer Res. 2014;16:R75.CrossRefPubMedPubMedCentral
24.
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001;412:346–51.CrossRefPubMed
25.
Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell. 2004;14:289–301.CrossRefPubMed
26.
Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. J Biol Chem. 2007;282:4102–12.CrossRefPubMed
27.
Petroski MD, Zhou X, Dong G, Daniel-Issakani S, Payan DG, Huang J. Substrate modification with lysine 63-linked ubiquitin chains through the UBC13-UEV1A ubiquitin-conjugating enzyme. J Biol Chem. 2007;282:29936–45.CrossRefPubMed
28.
Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009;461:114–9.CrossRefPubMedPubMedCentral
29.
Sun L, Li H, Chen J, Dehennaut V, Zhao Y, Yang Y, et al. A SUMOylation-dependent pathway regulates SIRT1 transcription and lung cancer metastasis. J Natl Cancer Inst. 2013;105:887–98.CrossRefPubMed
30.
31.
Fullgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature. 2013;500:468–71.CrossRefPubMedPubMedCentral
32.
Ryall JG, Dell'Orso S, Derfoul A, Juan A, Zare H, Feng XS, et al. The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell. 2015;16:171–83.CrossRefPubMedPubMedCentral
33.
Pulvino M, Liang Y, Oleksyn D, DeRan M, Van Pelt E, Shapiro J, et al. Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A. Blood. 2012;120:1668–77.CrossRefPubMedPubMedCentral
34.
35.
36.
37.
38.
Qi J, Yu Y, Akilli Ozturk O, Holland JD, Besser D, Fritzmann J, et al. New Wnt/beta-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals. Gut. 2015;65:1690–1701.
39.
Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, et al. MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut. 2013;62:1315–1326.
40.
Bronsert P, Enderle-Ammour K, Bader M, Timme S, Kuehs M, Csanadi A, et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol. 2014;234:410–22.CrossRefPubMed
41.
42.
Grimm WA, Messer JS, Murphy SF, Nero T, Lodolce JP, Weber CR, et al. The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon. Gut. 2016;65:456–64.CrossRefPubMed
43.
44.
45.
Catalano M, D'Alessandro G, Lepore F, Corazzari M, Caldarola S, Valacca C, et al. Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. Mol Oncol. 2015;9:1612–25.CrossRefPubMedPubMedCentral
46.
Cicchini M, Chakrabarti R, Kongara S, Price S, Nahar R, Lozy F, et al. Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy. 2014;10:2036–52.CrossRefPubMedPubMedCentral
47.
Li JP, Yang YX, Liu QL, Zhou ZW, Pan ST, He ZX, et al. The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells. Drug Des Devel Ther. 2015;9:1027–62.PubMedPubMedCentral
48.
49.
Lv Q, Hua F, Hu ZW. DEDD, a novel tumor repressor, reverses epithelial-mesenchymal transition by activating selective autophagy. Autophagy. 2012;8:1675–6.CrossRefPubMedPubMedCentral
50.
Lv Q, Wang W, Xue J, Hua F, Mu R, Lin H, et al. DEDD interacts with PI3KC3 to activate autophagy and attenuate epithelial-mesenchymal transition in human breast cancer. Cancer Res. 2012;72:3238–50.CrossRefPubMed
51.
Grassi G, Di Caprio G, Santangelo L, Fimia GM, Cozzolino AM, Komatsu M, et al. Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation. Cell Death Dis. 2015;6:e1880.CrossRefPubMedPubMedCentral
Metadata
Title
Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy
Authors
Tong Shen
Ling-Dong Cai
Yu-Hong Liu
Shi Li
Wen-Juan Gan
Xiu-Ming Li
Jing-Ru Wang
Peng-Da Guo
Qun Zhou
Xing-Xing Lu
Li-Na Sun
Jian-Ming Li
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2018
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-018-0638-9

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