Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2022

Open Access 01-12-2022 | Metastasis | Research

Targeting E2 ubiquitin-conjugating enzyme UbcH5c by small molecule inhibitor suppresses pancreatic cancer growth and metastasis

Authors: Simin Qi, Xiaoqing Guan, Jia Zhang, Dehua Yu, Xuefei Yu, Qinglin Li, Wenjuan Yin, Xiang-Dong Cheng, Weidong Zhang, Jiang-Jiang Qin

Published in: Molecular Cancer | Issue 1/2022

Login to get access

Abstract

Background

Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet.

Methods

Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR.

Results

UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models.

Conclusions

These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.
Appendix
Available only for authorised users
Literature
1.
2.
Strobel O, Neoptolemos J, Jäger D, Büchler MW. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol. 2019;16:11–26.PubMedCrossRef
3.
Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol. 2018;15:333–48.PubMedCrossRef
4.
Christenson ES, Jaffee E, Azad NS. Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future. Lancet Oncol. 2020;21:e135–45.PubMedPubMedCentralCrossRef
5.
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317–27.PubMedPubMedCentralCrossRef
6.
Deng L, Meng T, Chen L, Wei W, Wang P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther. 2020;5:11.PubMedPubMedCentralCrossRef
7.
Celebi G, Kesim H, Ozer E, Kutlu O. The effect of dysfunctional ubiquitin enzymes in the pathogenesis of most common diseases. Int J Mol Sci. 2020;21:6335.PubMedCentralCrossRef
8.
Berndsen CE, Wolberger C. New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol. 2014;21:301–7.PubMedCrossRef
9.
Cong H, Xu L, Wu Y, Qu Z, Bian T, Zhang W, et al. Inhibitor of apoptosis protein (IAP) antagonists in anticancer agent discovery: Current status and perspectives. J Med Chem. 2019;62:5750–72.PubMedCrossRef
10.
Qi SM, Cheng G, Cheng XD, Xu Z, Xu B, Zhang WD, et al. Targeting USP7-mediated deubiquitination of MDM2/MDMX-p53 pathway for cancer therapy: Are we there yet? Front Cell Dev Biol. 2020;8:233.PubMedPubMedCentralCrossRef
11.
Wang W, Qin JJ, Rajaei M, Li X, Yu X, Hunt C, et al. Targeting MDM2 for novel molecular therapy: Beyond oncology. Med Res Rev. 2020;40:856–80.PubMedCrossRef
12.
Kumar S, Fairmichael C, Longley DB, Turkington RC. The multiple roles of the IAP super-family in cancer. Pharmacol Ther. 2020;214:107610.PubMedCrossRef
13.
Gao X, Zhang L, Wei Y, Yang Y, Li J, Wu H, et al. Prognostic value of XIAP level in patients with various cancers: A systematic review and meta-analysis. J Cancer. 2019;10:1528–37.PubMedPubMedCentralCrossRef
14.
15.
Blaquiere N, Villemure E, Staben ST. Medicinal chemistry of inhibiting RING-type E3 ubiquitin ligases. J Med Chem. 2020;63:7957–85.PubMedCrossRef
16.
Du X, Song H, Shen N, Hua R, Yang G. The molecular basis of ubiquitin-conjugating enzymes (E2s) as a potential target for cancer therapy. Int J Mol Sci. 2021;22:3440.PubMedPubMedCentralCrossRef
17.
Zhao ZK, Wu WG, Chen L, Dong P, Gu J, Mu JS, et al. Expression of UbcH10 in pancreatic ductal adenocarcinoma and its correlation with prognosis. Tumour Biol. 2013;34:1473–7.PubMedCrossRef
18.
Wang X, Yin L, Yang L, Zheng Y, Liu S, Yang J, et al. Silencing ubiquitin-conjugating enzyme 2C inhibits proliferation and epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma. FEBS J. 2019;286:4889–909.PubMedCrossRef
19.
Zheng YW, Gao PF, Ma MZ, Chen Y, Li CY. Role of ubiquitin-conjugating enzyme E2T in the carcinogenesis and progression of pancreatic cancer. Oncol Lett. 2020;20:1462–8.PubMedPubMedCentralCrossRef
20.
Wang L, Liang Y, Li P, Liang Q, Sun H, Xu D, et al. Oncogenic activities of UBE2S mediated by VHL/HIF-1alpha/STAT3 signal via the ubiquitin-proteasome system in PDAC. Onco Targets Ther. 2019;12:9767–81.PubMedPubMedCentralCrossRef
21.
Shang M, Weng L, Xu G, Wu S, Liu B, Yin X, et al. TRIM11 suppresses ferritinophagy and gemcitabine sensitivity through UBE2N/TAX1BP1 signaling in pancreatic ductal adenocarcinoma. J Cell Physiol. 2021;236:6868–83.PubMedCrossRef
22.
Nie LY, Qin JJ, Huang Y, Yan L, Liu YB, Pan YX, et al. Sesquiterpenoids from Inula lineariifolia inhibit nitric oxide production. J Nat Prod. 2010;73:1117–20.PubMedCrossRef
23.
Wang W, Qin JJ, Voruganti S, Nijampatnam B, Velu SE, Ruan KH, et al. Discovery and characterization of dual inhibitors of MDM2 and NFAT1 for pancreatic cancer therapy. Cancer Res. 2018;78:5656–67.PubMedPubMedCentralCrossRef
24.
Wang W, Qin JJ, Voruganti S, Wang MH, Sharma H, Patil S, et al. Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. Gastroenterology. 2014;147:893–902.PubMedCrossRef
25.
Wang W, Qin JJ, Voruganti S, Srivenugopal KS, Nag S, Patil S, et al. The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun. 2014;5:5086.PubMedCrossRef
26.
Wang W, Cheng JW, Qin JJ, Hu B, Li X, Nijampatnam B, et al. MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53. Cancer Lett. 2019;459:156–67.PubMedPubMedCentralCrossRef
27.
Zhang J, Wang W, Zhou Y, Yang J, Xu J, Xu Z, et al. Terphenyllin suppresses orthotopic pancreatic tumor growth and prevents metastasis in mice. Front Pharmacol. 2020;11:457.PubMedPubMedCentralCrossRef
28.
Guan X, Cai M, Du Y, Yang E, Ji J, Wu J. CVCDAP: an integrated platform for molecular and clinical analysis of cancer virtual cohorts. Nucleic Acids Res. 2020;48:W463–71.PubMedPubMedCentralCrossRef
29.
Zhou Y, Chen R, Luo X, Zhang WD, Qin JJ. The E2 ubiquitin-conjugating enzyme UbcH5c: an emerging target in cancer and immune disorders. Drug Discov Today. 2020;25:1988–97.CrossRef
30.
Liu L, Hua Y, Wang D, Shan L, Zhang Y, Zhu J, et al. A sesquiterpene lactone from a medicinal herb inhibits proinflammatory activity of TNF-alpha by inhibiting ubiquitin-conjugating enzyme UbcH5. Chem Biol. 2014;21:1341–50.PubMedCrossRef
31.
Qin JJ, Wang W, Voruganti S, Wang H, Zhang WD, Zhang R. Identification of a new class of natural product MDM2 inhibitor: In vitro and in vivo anti-breast cancer activities and target validation. Oncotarget. 2015;6:2623–40.PubMedCrossRef
32.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.PubMedPubMedCentralCrossRef
33.
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.PubMedPubMedCentralCrossRef
34.
Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol. 2020;17:527–40.PubMedPubMedCentralCrossRef
35.
Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020;17:487–505.PubMedPubMedCentralCrossRef
36.
Collisson EA, Bailey P, Chang DK, Biankin AV. Molecular subtypes of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2019;16:207–20.PubMedCrossRef
37.
Zhang S, Zhou Y, Sarkeshik A, Yates JR, Thomson TM, Zhang Z, et al. Identification of RNF8 as a ubiquitin ligase involved in targeting the p12 subunit of DNA polymerase δ for degradation in response to DNA damage. J Biol Chem. 2013;288:2941–50.PubMedCrossRef
38.
Nara M, Teshima K, Watanabe A, Ito M, Iwamoto K, Kitabayashi A, et al. Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells. PLoS One. 2013;8:e56954.PubMedPubMedCentralCrossRef
39.
Huang XH, Yan X, Zhang QH, Hong P, Zhang WX, Liu YP, et al. Direct targeting of HSP90 with daurisoline destabilizes β-catenin to suppress lung cancer tumorigenesis. Cancer Lett. 2020;489:66–78.PubMedCrossRef
40.
Chen H, Wu G, Gao S, Guo R, Zhao Z, Yuan H, et al. Discovery of potent small-molecule inhibitors of ubiquitin-conjugating enzyme UbcH5c from α-santonin derivatives. J Med Chem. 2017;60:6828–52.PubMedCrossRef
41.
Huang M, Zhou Y, Duan D, Yang C, Zhou Z, Li F, et al. Targeting ubiquitin conjugating enzyme UbcH5b by a triterpenoid PC3-15 from Schisandra plants sensitizes triple-negative breast cancer cells to lapatinib. Cancer Lett. 2021;504:125–36.PubMedCrossRef
42.
Qin JJ, Jin HZ, Huang Y, Zhang SD, Shan L, Voruganti S, et al. Selective cytotoxicity, inhibition of cell cycle progression, and induction of apoptosis in human breast cancer cells by sesquiterpenoids from Inula lineariifolia Turcz. Eur J Med Chem. 2013;68:473–81.PubMedPubMedCentralCrossRef
43.
Wu G, Zhu L, Yuan X, Chen H, Xiong R, Zhang S, et al. Britanin ameliorates cerebral ischemia-reperfusion injury by inducing the Nrf2 protective pathway. Antioxid Redox Signal. 2017;27:754–68.PubMedCrossRef
44.
Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24.PubMedCrossRef
45.
Tundo GR, Sbardella D, Santoro AM, Coletta A, Oddone F, Grasso G, et al. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges. Pharmacol Ther. 2020;213:107579.PubMedPubMedCentralCrossRef
46.
Antonia RJ, Hagan RS, Baldwin AS. Expanding the view of IKK: New substrates and new biology. Trends Cell Biol. 2021;31:166–78.PubMedCrossRef
47.
Eluard B, Thieblemont C, Baud V. NF-κB in the new era of cancer therapy. Trends Cancer. 2020;6:677–87.PubMedCrossRef
48.
Li Y, Sun XX, Elferich J, Shinde U, David LL, Dai MS. Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (Otub1) to suppress UbcH5 enzyme and stabilize p53 protein. J Biol Chem. 2014;289:5097–108.PubMedPubMedCentralCrossRef
49.
Peng H, Yang J, Li G, You Q, Han W, Li T, et al. Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Res. 2017;27:657–74.PubMedPubMedCentralCrossRef
50.
Yang N, Chen T, Wang L, Liu R, Niu Y, Sun L, et al. CXCR4 mediates matrix stiffness-induced downregulation of UBTD1 driving hepatocellular carcinoma progression via YAP signaling pathway. Theranostics. 2020;10:5790–801.PubMedPubMedCentralCrossRef
Metadata
Title
Targeting E2 ubiquitin-conjugating enzyme UbcH5c by small molecule inhibitor suppresses pancreatic cancer growth and metastasis
Authors
Simin Qi
Xiaoqing Guan
Jia Zhang
Dehua Yu
Xuefei Yu
Qinglin Li
Wenjuan Yin
Xiang-Dong Cheng
Weidong Zhang
Jiang-Jiang Qin
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2022
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-022-01538-4

Other articles of this Issue 1/2022

Molecular Cancer 1/2022 Go to the issue

Research

The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin

Research

Antibody-mediated delivery of a viral MHC-I epitope into the cytosol of target tumor cells repurposes virus-specific CD8+ T cells for cancer immunotherapy

Correction

Correction: lncRNA-PLACT1 sustains activation of NF-κB pathway through a positive feedback loop with IκBα/E2F1 axis in pancreatic cancer

Research

Tumor-suppressive circRHOBTB3 is excreted out of cells via exosome to sustain colorectal cancer cell fitness

Review

Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

Research

Targeting SOST using a small-molecule compound retards breast cancer bone metastasis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits