The crosstalk between ubiquitin-conjugating enzyme E2Q1 and p53 in colorectal cancer: An in vitro analysis.
Bcl2
Colorectal neoplasms
Cyclin E
Mdm2
Tumor suppressor protein p53
UBE2Q1
Journal
Medical oncology (Northwood, London, England)
ISSN: 1559-131X
Titre abrégé: Med Oncol
Pays: United States
ID NLM: 9435512
Informations de publication
Date de publication:
09 Jun 2023
09 Jun 2023
Historique:
received:
06
01
2023
accepted:
25
04
2023
medline:
12
6
2023
pubmed:
9
6
2023
entrez:
9
6
2023
Statut:
epublish
Résumé
Colorectal cancer (CRC) is a prevalent gastrointestinal neoplasm that ranks fourth in terms of cancer-related deaths worldwide. In the process of CRC progression, multiple ubiquitin-conjugating enzymes (E2s) are involved; UBE2Q1 is one of those newly identified E2s that is markedly expressed in human colorectal tumors. Since p53 is a well-known tumor suppressor and defined as a key factor to be targeted by the ubiquitin-proteasome system, we hypothesized that UBE2Q1 might contribute to CRC progression through the modulation of p53. Using the lipofection method, the cultured SW480 and LS180 cells were transfected with the UBE2Q1 ORF-containing pCMV6-AN-GFP vector. Then, quantitative RT-PCR was used to assay the mRNA expression levels of p53's target genes, i.e., Mdm2, Bcl2, and Cyclin E. Moreover, Western blot analysis was performed to confirm the cellular overexpression of UBE2Q1 and assess the protein levels of p53, pre- and post-transfection. The expression of p53's target genes were cell line-dependent except for Mdm2 that was consistent with the findings of p53. The results of Western blotting demonstrated that the protein levels of p53 were greatly lower in UBE2Q1-transfected SW480 cells compared to the control SW480 cells. However, the reduced levels of p53 protein were not remarkable in the transfected LS180 cells compared to the control cells. The suppression of p53 is believed to be the result of UBE2Q1-dependent ubiquitination and its subsequent proteasomal degradation. Furthermore, the ubiquitination of p53 can act as a signal for degradation-independent functions, such as nuclear export and suppressing the p53's transcriptional activities. In this context, the decreased Mdm2 levels can moderate the proteasome-independent mono-ubiquitination of p53. The ubiquitinated p53 modulates the transcriptional levels of target genes. Therefore, the up-modulation of UBE2Q1 may influence the transcriptional activities depending on p53, and thereby contributes to CRC progression through regulating the p53.
Identifiants
pubmed: 37294480
doi: 10.1007/s12032-023-02039-0
pii: 10.1007/s12032-023-02039-0
doi:
Substances chimiques
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Proteasome Endopeptidase Complex
EC 3.4.25.1
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
UBE2Q1 protein, human
EC 2.3.2.23
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
199Subventions
Organisme : Vice-Chancellor for Research, Shiraz University of Medical Sciences
ID : 93-05-29-7123
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Kadkhoda S, Taslimi R, Noorbakhsh F, Darbeheshti F, Bazzaz JT, Ghafouri-Fard S, et al. Importance of Circ0009910 in colorectal cancer pathogenesis as a possible regulator of miR-145 and PEAK1. World J Surg Oncol. 2021;19(1):1–11.
Sinicrope FA. Increasing incidence of early-onset colorectal cancer. N Engl J Med. 2022;386(16):1547–58.
pubmed: 35443109
Cho YA, Lee J, Oh JH, Chang HJ, Sohn DK, Shin A, et al. Genetic risk score, combined lifestyle factors and risk of colorectal cancer. Cancer Res Treat: Off J Korean Cancer Assoc. 2019;51(3):1033–40.
Dolatkhah R, Somi MH, Kermani IA, Ghojazadeh M, Jafarabadi MA, Farassati F, et al. Increased colorectal cancer incidence in Iran: a systematic review and meta-analysis. BMC Public Health. 2015;15(1):1–14.
Lizarbe MA, Calle-Espinosa J, Fernández-Lizarbe E, Fernández-Lizarbe S, Robles MÁ, Olmo N, et al. Colorectal cancer: from the genetic model to posttranscriptional regulation by noncoding RNAs. BioMed Res Int. 2017. https://doi.org/10.1038/s41418-022-00989-y .
doi: 10.1038/s41418-022-00989-y
pubmed: 28573140
pmcid: 5442347
Kennedy MC, Lowe SW. Mutant p53: it’s not all one and the same. Cell Death Differ. 2022;29(5):983–7.
pubmed: 35361963
pmcid: 9090915
Liebl MC, Hofmann TG. The role of p53 signaling in colorectal cancer. Cancers. 2021;13(9):2125.
pubmed: 33924934
pmcid: 8125348
Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8(4):275–83.
pubmed: 17380161
Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15(1):13–30.
pubmed: 28948977
Lacroix M, Toillon R-A, Leclercq G. p53 and breast cancer, an update. Endocr Relat Cancer. 2006;13(2):293–325.
pubmed: 16728565
Tokino T, Nakamura Y. The role of p53-target genes in human cancer. Crit Rev Oncol Hematol. 2000;33(1):1–6.
pubmed: 10714958
Ravizza R, Gariboldi MB, Passarelli L, Monti E. Role of the p53/p21 system in the response of human colon carcinoma cells to Doxorubicin. BMC Cancer. 2004;4(1):92.
pubmed: 15601469
pmcid: 544559
Yang Y, Li C-CH, Weissman AM. Regulating the p53 system through ubiquitination. Oncogene. 2004;23(11):2096–106.
pubmed: 15021897
Mani A, Gelmann EP. The ubiquitin-proteasome pathway and its role in cancer. J Clin Oncol. 2005;23(21):4776–89.
pubmed: 16034054
Saffari-Chaleshtori J, Asadi-Samani M, Rasouli M, Shafiee SM. Autophagy and ubiquitination as two major players in colorectal cancer: a review on recent patents. Recent Pat Anti-Cancer Drug Discov. 2020;15(2):143–53.
Dahlmann B. Role of proteasomes in disease. BMC Biochem. 2007;8(Suppl 1):S3.
pubmed: 18047740
pmcid: 2106367
Brooks CL, Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol. 2003;15(2):164–71.
pubmed: 12648672
Moll UM, Petrenko O. The MDM2-p53 interaction. Mol Cancer Res. 2003;1(14):1001–8.
pubmed: 14707283
Saville MK, Sparks A, Xirodimas DP, Wardrop J, Stevenson LF, Bourdon J-C, et al. Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. J Biol Chem. 2004;279(40):42169–81.
pubmed: 15280377
Brooks CL, Gu W. p53 regulation by ubiquitin. FEBS Lett. 2011;585(18):2803–9.
pubmed: 21624367
pmcid: 3172401
Pant V, Lozano G. Limiting the power of p53 through the ubiquitin proteasome pathway. Genes Dev. 2014;28(16):1739–51.
pubmed: 25128494
pmcid: 4197966
Bremm A, Komander D. Emerging roles for Lys11-linked polyubiquitin in cellular regulation. Trends Biochem Sci. 2011;36(7):355–63.
pubmed: 21641804
Tang X-K, Wang K-J, Tang Y-K, Chen L. Effects of ubiquitin-conjugating enzyme 2C on invasion, proliferation and cell cycling of lung cancer cells. Asian Pac J Cancer Prev: APJCP. 2013;15(7):3005–9.
Waite KA, Eng C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. 2003;12(6):679–84.
pubmed: 12620973
Gerard B, Sanders MA, Visscher DW, Tait L, Shekhar MP. (2012) Lysine394 is a novel Rad6B-induced ubiquitination site on beta-catenin. Biochim et Biophys Acta (BBA)-Mol Cell Res. 1823;10:1686–96.
Seghatoleslam A, Nikseresht M, Shafiee SM, Monabati A, Namavari MM, Talei A, et al. Expression of the novel human gene, UBE2Q1, in breast tumors. Mol Biol Rep. 2012;39(5):5135–41.
pubmed: 22167327
Nikseresht M, Seghatoleslam A, Monabati A, Talei A, Ghalati FB, Owji AA. Overexpression of the novel human gene, UBE2Q2, in breast cancer. Cancer Genet Cytogenet. 2010;197(2):101–6.
pubmed: 20193842
Shafiee SM, Seghatoleslam A, Nikseresht M, Hosseini SV, Alizadeh-Naeeni M, Safaei A, et al. UBE2Q1 expression in human colorectal tumors and cell lines. Mol Biol Rep. 2013;40(12):7045–51.
pubmed: 24197692
Shafiee SM, Seghatoleslam A, Nikseresht M, Hosseini SV, Alizadeh-Naeeni M, Safaei A, et al. Expression Status of UBE2Q2 in colorectal primary tumors and cell lines. Iranian J Med Sci. 2014;39(2 Suppl):196.
Seghatoleslam A, Bozorg-Ghalati F, Monabati A, Nikseresht M, Owji AA. UBE2Q1, as a down regulated gene in pediatric acute lymphoblastic leukemia. Int J Mol Cell Med. 2014;3(2):95.
pubmed: 25035859
pmcid: 4082811
Bordbar M. Expression of UBE2Q2, a putative member of the ubiquitin-conjugating enzyme family in pediatric acute lymphoblastic leukemia. Arch Iran Med. 2012;15(6):352.
pubmed: 22642244
Seghatoleslam A, Zambrano A, Millon R, Ganguli G, Argentini M, Cromer A, et al. Analysis of a novel human gene, LOC92912, over-expressed in hypopharyngeal tumours. Biochem Biophys Res Commun. 2006;339(1):422–9.
pubmed: 16300736
Bai L, Zhu W-G. p53: structure, function and therapeutic applications. J Cancer Mol. 2006;2(4):141–53.
Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Can Res. 1994;54(12):3131–5.
Otsuka K, Ochiya T. Genetic networks lead and follow tumor development: microRNA regulation of cell cycle and apoptosis in the p53 pathways. BioMed Res Int. 2014. https://doi.org/10.1155/2014/749724 .
doi: 10.1155/2014/749724
pubmed: 25302307
pmcid: 4180389
Lee J, Gu W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 2010;17(1):86–92.
pubmed: 19543236
DeVine T, Dai M-S. Targeting the ubiquitin-mediated proteasome degradation of p53 for cancer therapy. Curr Pharm Des. 2013;19(18):3248.
pubmed: 23151129
pmcid: 3637405
Lai Z, Yang T, Kim YB, Sielecki TM, Diamond MA, Strack P, et al. Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors. Proc Natl Acad Sci. 2002;99(23):14734–9.
pubmed: 12407176
pmcid: 137488
Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26(12):1268–86.
pubmed: 22713868
pmcid: 3387655
Strano S, Dell’Orso S, Di Agostino S, Fontemaggi G, Sacchi A, Blandino G. Mutant p53: an oncogenic transcription factor. Oncogene. 2007;26(15):2212–9.
pubmed: 17401430
Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, et al. Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell. 2006;10(3):191–202.
pubmed: 16959611
Rochette PJ, Bastien N, Lavoie J, Guérin SL, Drouin R. SW480, a p53 double-mutant cell line retains proficiency for some p53 functions. J Mol Biol. 2005;352(1):44–57.
pubmed: 16061257
Shafiee S, Rasti M, Seghatoleslam A, Azimi T, Owji A. UBE2Q1 in a human breast carcinoma cell line: overexpression and interaction with p53. Asian Pac J Cancer Prev: APJCP. 2014;16(9):3723–7.
Ahmed D, Eide P, Eilertsen I, Danielsen S, Eknaes M, Hektoen M, et al. Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis. 2013;2(9): e71.
pubmed: 24042735
pmcid: 3816225
Yoon W-H, Lee S-K, Song K-S, Kim J-S, Kim T-D, Li G, et al. The tumorigenic, invasive and metastatic potential of epithelial and round subpopulations of the SW480 human colon cancer cell line. Mol Med Rep. 2008;1(5):763–8.
pubmed: 21479483
Lukashchuk N, Vousden KH. Ubiquitination and degradation of mutant p53. Mol Cell Biol. 2007;27(23):8284–95.
pubmed: 17908790
pmcid: 2169174
Rodriguez MS, Desterro JM, Lain S, Lane DP, Hay RT. Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol Cell Biol. 2000;20(22):8458–67.
pubmed: 11046142
pmcid: 102152
Love IM, Grossman SR. it takes 15 to tango making sense of the many ubiquitin ligases of p53. Genes Cancer. 2012;3(3–4):249–63.
pubmed: 23150758
pmcid: 3494362
Esser C, Scheffner M, Höhfeld J. The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem. 2005;280(29):27443–8.
pubmed: 15911628
Grelle G, Kostka S, Otto A, Kersten B, Genser KF, Müller E-C, et al. Identification of VCP/p97, carboxyl terminus of Hsp70-interacting protein (CHIP), and amphiphysin II interaction partners using membrane-based human proteome arrays. Mol Cell Proteomics. 2006;5(2):234–44.
pubmed: 16275660
Min J-N, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C. CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol. 2008;28(12):4018–25.
pubmed: 18411298
pmcid: 2423116
Kruse J-P, Gu W. MSL2 promotes Mdm2-independent cytoplasmic localization of p53. J Biol Chem. 2009;284(5):3250–63.
pubmed: 19033443
pmcid: 2631942
Laine A, Ze R. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene. 2007;26(10):1477–83.
pubmed: 16924229
Laine A, Topisirovic I, Zhai D, Reed JC, Borden KL, Ze R. Regulation of p53 localization and activity by Ubc13. Mol Cell Biol. 2006;26(23):8901–13.
pubmed: 17000756
pmcid: 1636826
Nie L, Sasaki M, Maki CG. Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination. J Biol Chem. 2007;282(19):14616–25.
pubmed: 17371868
Brooks CL, Gu W. Dynamics in the p53-Mdm2 ubiquitination pathway. Cell Cycle. 2004;3(7):893–7.
Chang R, Wei L, Lu Y, Cui X, Lu C, Liu L, et al. Upregulated expression of ubiquitin-conjugating enzyme E2Q1 (UBE2Q1) is associated with enhanced cell proliferation and poor prognosis in human hapatocellular carcinoma. J Mol Histol. 2015;46(1):45–56.
pubmed: 25311764
Wan C, Chen J, Hu B, Zou H, Li A, Guo A, et al. Downregulation of UBE2Q1 is associated with neuronal apoptosis in rat brain cortex following traumatic brain injury. J Neurosci Res. 2014;92(1):1–12.
pubmed: 24166684
Laptenko O, Prives C. Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ. 2006;13(6):951–61.
pubmed: 16575405
Hemann M, Lowe S. The p53–Bcl-2 connection. Cell Death Differ. 2006;13(8):1256–9.
pubmed: 16710363
Koehler BC, Scherr A-L, Lorenz S, Urbanik T, Kautz N, Elssner C, et al. Beyond cell death—Antiapoptotic bcl-2 proteins regulate migration and invasion of colorectal cancer cells in vitro. PLoS ONE. 2013;8(10):e76446.
pubmed: 24098503
pmcid: 3789675
Simone C, Resta N, Bagella L, Giordano A, Guanti G. Cyclin E and chromosome instability in colorectal cancer cell lines. Mol Pathol. 2002;55(3):200.
pubmed: 12032232
pmcid: 1187174
Di Agostino S, Sorrentino G, Ingallina E, Valenti F, Ferraiuolo M, Bicciato S, et al. YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins. EMBO Rep. 2016;17(2):188–201.
pubmed: 26691213
Alam S, Yadav V, Bajaj S, Datta A, Dutta S, Bhattacharyya M, et al. DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. Cell Death Differ. 2016;23(4):707–22.
pubmed: 26494468
Zhang P, Zuo Z, Wu A, Shang W, Bi R, Jin Q, et al. miR-600 inhibits cell proliferation, migration and invasion by targeting p53 in mutant p53-expressing human colorectal cancer cell lines. Oncol Lett. 2017;13(3):1789–96.
pubmed: 28454325
pmcid: 5403669
Fahmidehkar MA, Shafiee SM, Eftekhar E, Mahbudi L, Seghatoleslam A. Induction of cell proliferation, clonogenicity and cell accumulation in S phase as a consequence of human UBE2Q1 overexpression. Oncol Lett. 2016;12(3):2169–74.
pubmed: 27602158
pmcid: 4998499