Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7-APEH-Proteasome Axis in High-grade Serous Ovarian Carcinoma.
Animals
Cell Line, Tumor
Cystadenocarcinoma, Serous
/ drug therapy
Female
Gene Expression Profiling
/ methods
Gene Expression Regulation, Neoplastic
Humans
Indoles
/ pharmacology
Kaplan-Meier Estimate
Mice, Nude
Neoplasm Grading
Ovarian Neoplasms
/ drug therapy
Oximes
/ pharmacology
Peptide Hydrolases
/ genetics
Proteasome Endopeptidase Complex
/ genetics
Proteostasis
/ genetics
Ubiquitin Thiolesterase
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
/ methods
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
09
10
2020
revised:
10
02
2021
accepted:
17
03
2021
pubmed:
24
3
2021
medline:
27
1
2022
entrez:
23
3
2021
Statut:
ppublish
Résumé
High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the
Identifiants
pubmed: 33753553
pii: 1541-7786.MCR-20-0883
doi: 10.1158/1541-7786.MCR-20-0883
doi:
Substances chimiques
Indoles
0
LDN 57444
0
Oximes
0
APEH protein, human
EC 3.4.-
Peptide Hydrolases
EC 3.4.-
Ubiquitin Thiolesterase
EC 3.4.19.12
PSMA7 protein, human
EC 3.4.25.1
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1168-1181Informations de copyright
©2021 American Association for Cancer Research.
Références
Schubert U, Antón LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature. 2000;404:770–4.
Guang MHZ, Kavanagh EL, Dunne LP, Dowling P, Zhang L, Lindsay S, et al. Targeting proteotoxic stress in cancer: a review of the role that protein quality control pathways play in oncogenesis. Cancers. 2019;11:66.
Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26:199–212.
Donnelly N, Storchová Z. Aneuploidy and proteotoxic stress in cancer. Mol Cell Oncol. 2015;2:e976491.
Bastola P, Oien DB, Cooley M, Chien J. Emerging cancer therapeutic targets in protein homeostasis. AAPS J. 2018;20:94.
Reeg S, Jung T, Castro JP, Davies KJA, Henze A, Grune T. The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome. Free Radic Biol Med. 2016;99:153–66.
Roeten MSF, Cloos J, Jansen G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother Pharmacol. 2018;81:227–43.
Naujokat C, Hoffmann S. Role and function of the 26S proteasome in proliferation and apoptosis. Lab Invest. 2002;82:965–80.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–16.
Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17:1374–95.
Suraweera A, Münch C, Hanssum A, Bertolotti A. Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol Cell. 2012;48:242–53.
Xu H, Han H, Song S, Yi N, Qian C, Qiu Y, et al. Exosome-transmitted PSMA3 and PSMA3-AS1 promote proteasome inhibitor resistance in multiple myeloma. Clin Cancer Res. 2019;25:1923–35.
Ali A, Wang Z, Fu J, Ji L, Liu J, Li L, et al. Differential regulation of the REGgamma-proteasome pathway by p53/TGF-beta signalling and mutant p53 in cancer cells. Nat Commun. 2013;4:2667.
Chondrogianni N, Tzavelas C, Pemberton AJ, Nezis IP, Rivett AJ, Gonos ES. Overexpression of proteasome beta5 assembled subunit increases the amount of proteasome and confers ameliorated response to oxidative stress and higher survival rates. J Biol Chem. 2005;280:11840–50.
Zhang X, Schulz R, Edmunds S, Krüger E, Markert E, Gaedcke J, et al. MicroRNA-101 suppresses tumor cell proliferation by acting as an endogenous proteasome inhibitor via targeting the proteasome assembly factor POMP. Mol Cell. 2015;59:243–57.
Harris IS, Endress JE, Coloff JL, Selfors LM, McBrayer SK, Rosenbluth JM, et al. Deubiquitinases maintain protein homeostasis and survival of cancer cells upon glutathione depletion. Cell Metab. 2019;29:1166–81.
Mofers A, Pellegrini P, Linder S, D'Arcy P. Proteasome-associated deubiquitinases and cancer. Cancer Metastasis Rev. 2017;36:635–53.
Setsuie R, Wada K. The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int. 2007;51:105–11.
Lombardino AJ, Li X-C, Hertel M, Nottebohm F. Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. Proc Natl Acad Sci U S A. 2005;102:8036–41.
Graham SH, Liu H. Life and death in the trash heap: the ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia. Ageing Res Rev. 2017;34:30–8.
Goto Y, Zeng L, Yeom CJ, Zhu Y, Morinibu A, Shinomiya K, et al. UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1alpha. Nat Commun. 2015;6:6153.
Kwan SY, Au-Yeung CL, Yeung TL, Rynne-Vidal A, Wong KK, Risinger JI, et al. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) promotes uterine serous cancer cell proliferation and cell cycle progression. Cancers. 2020;12:118.
Hussain S, Bedekovics T, Chesi M, Bergsagel PL, Galardy PJ. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression. Oncotarget. 2015;6:40704–18.
Liu S, González-Prieto R, Zhang M, Geurink PP, Kooij R, Iyengar PV, et al. Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis. Clin Cancer Res. 2020;26:1460–73.
Ummanni R, Jost E, Braig M, Lohmann F, Mundt F, Barett C, et al. Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation. Mol Cancer. 2011;10:129.
Okochi-Takada E, Nakazawa K, Wakabayashi M, Mori A, Ichimura S, Yasugi T, et al. Silencing of the UCHL1 gene in human colorectal and ovarian cancers. Int J Cancer. 2006;119:1338–44.
Bowtell DD, Böhm S, Ahmed AA, Aspuria P-J, Bast RC, Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15:668–79.
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6:1–6.
Gyorffy B, Lanczky A, Szallasi Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19:197–208.
Madden SF, Clarke C, Stordal B, Carey MS, Broaddus R, Gallagher WM, et al. OvMark: a user-friendly system for the identification of prognostic biomarkers in publicly available ovarian cancer gene expression datasets. Mol Cancer. 2014;13:241.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
Ladanyi A, Mukherjee A, Kenny HA, Johnson A, Mitra AK, Sundaresan S, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene. 2018;37:2285–301.
Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015;525:206–11.
Iwanicki MP, Chen HY, Iavarone C, Zervantonakis IK, Muranen T, Novak M, et al. Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition. JCI Insight. 2016;1:e86829.
Tomar S, Plotnik JP, Haley J, Scantland J, Dasari S, Sheikh Z, et al. ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase. Cancer Lett. 2018;414:190–204.
Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol. 2016;18:897–909.
Palumbo R, Gogliettino M, Cocca E, Iannitti R, Sandomenico A, Ruvo M, et al. APEH inhibition affects osteosarcoma cell viability via downregulation of the proteasome. Int J Mol Sci. 2016;17:1614.
Singh KP, Treas J, Tyagi T, Gao W. DNA demethylation by 5-aza-2-deoxycytidine treatment abrogates 17 beta-estradiol-induced cell growth and restores expression of DNA repair genes in human breast cancer cells. Cancer Lett. 2012;316:62–9.
Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.
Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.
Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.
Mitra S, Tiwari K, Podicheti R, Pandhiri T, Rusch DB, Bonetto A, et al. Transcriptome profiling reveals matrisome alteration as a key feature of ovarian cancer progression. Cancers. 2019;11:1513.
Kuhn E, Kurman RJ, Vang R, Sehdev AS, Han G, Soslow R, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma–evidence supporting the clonal relationship of the two lesions. J Pathol. 2012;226:421–6.
Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.
Sanchez-Diaz PC, Chang JC, Moses ES, Dao Tu, Chen Y, Hung JY. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma. PLoS One. 2017;12:e0176879.
Hussain S, Bedekovics T, Ali A, Zaid O, May DG, Roux KJ, et al. A cysteine near the C-terminus of UCH-L1 is dispensable for catalytic activity but is required to promote AKT phosphorylation, eIF4F assembly, and malignant B-cell survival. Cell Death Discov. 2019;5:152.
Ilic A, Lu S, Bhatia V, Begum F, Klonisch T, Agarwal P, et al. Ubiquitin C-terminal hydrolase isozyme L1 is associated with shelterin complex at interstitial telomeric sites. Epigenetics Chromatin. 2017;10:54.
Zimmermann J, Erdmann D, Lalande I, Grossenbacher R, Noorani M, Fürst P. Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1. Oncogene. 2000;19:2913–20.
Padmanabhan A, Vuong SA, Hochstrasser M. Assembly of an evolutionarily conserved alternative proteasome isoform in human cells. Cell Rep. 2016;14:2962–74.
Chui MH, Doodnauth SA, Erdmann N, Tiedemann RE, Sircoulomb F, Drapkin R, et al. Chromosomal instability and mTORC1 activation through PTEN loss contribute to proteotoxic stress in ovarian carcinoma. Cancer Res. 2019;79:5536–49.
Su KH, Dai C. mTORC1 senses stresses: coupling stress to proteostasis. Bioessays. 2017;39:1600268.
Poondla N, Chandrasekaran AP, Kim K-S, Ramakrishna S. Deubiquitinating enzymes as cancer biomarkers: new therapeutic opportunities?. BMB Rep. 2019;52:181–9.
Sacco JJ, Coulson JM, Clague MJ, Urbé S. Emerging roles of deubiquitinases in cancer-associated pathways. IUBMB Life. 2010;62:140–57.
Bedekovics T, Hussain S, Feldman AL, Galardy PJ. UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma. Blood. 2016;127:1564–74.
Xiang T, Li L, Yin X, Yuan C, Tan C, Su X, et al. The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer. PLoS One. 2012;7:e29783.
D'Arcy P, Brnjic S, Olofsson MH, Fryknäs M, Lindsten K, De Cesare M, et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med. 2011;17:1636–40.
Alexandrova EM, Marchenko ND. Mutant p53 - heat shock response oncogenic cooperation: a new mechanism of cancer cell survival. Front Endocrinol. 2015;6:53.
Sicari D, Fantuz M, Bellazzo A, Valentino E, Apollonio M, Pontisso I, et al. Mutant p53 improves cancer cells' resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6. Oncogene. 2019;38:6184–95.
Schmidt RM, Schessner JP, Borner GH, Schuck S. The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote ER stress resistance. Elife. 2019;8:e43244.
Lü S, Chen Z, Yang J, Chen Li, Gong S, Zhou H, et al. Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line. Exp Hematol. 2008;36:1278–84.
Rowinsky EK, Paner A, Berdeja JG, Paba-Prada C, Venugopal P, Porkka K, et al. Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma. Invest New Drugs. 2020;38:1448–53.