UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas
- PMID: 38244540
- PMCID: PMC10897521
- DOI: 10.1016/j.xcrm.2023.101381
UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas
Abstract
Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.
Keywords: UCHL1; neuroblastoma; neuroendocrine carcinomas; neuroendocrine prostate cancer; nuclear pore complex; small cell lung cancer.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests E.C. is a consultant for Dotquant and received research funding under institutional SRAs from AbbVie, Astra Zeneca, Janssen Research, Gilead, Zenith Epigenetics, Forma Therapeutics, Bayer, Kronos, Foghorn, and MacroGenics. M.D. is a consultant for Regeneron, Beigene, Astra Zeneca, Sanofi/Genzyme, Eurofins, Janssen, and Genentech (uncompensated) and performs research at Merck, Genentech, CellSight, Novartis, AbbVie, United Therapeutics, Varian, Verily, and Celgene. J.H. is a consultant for or owns shares in Kingmed, MoreHealth, OptraScan, Genetron, Omnitura, Vetonco, York Biotechnology, Genecode, VIVA Biotech, and Sisu Pharma and received grants from Zenith Epigenetics, BioXcel Therapeutics, Inc., and Fortis Therapeutics. T.S. is a consultant for Dren Bio.
Figures








Similar articles
-
Ubiquitin C-terminal hydrolase-L1 has prognostic relevance and is a therapeutic target for high-grade neuroendocrine lung cancers.Cancer Sci. 2020 Feb;111(2):610-620. doi: 10.1111/cas.14284. Epub 2020 Jan 19. Cancer Sci. 2020. PMID: 31845438 Free PMC article.
-
Clinical significance of promoter methylation status of tumor suppressor genes in circulating DNA of pancreatic cancer patients.J Cancer Res Clin Oncol. 2020 Apr;146(4):897-907. doi: 10.1007/s00432-020-03169-y. Epub 2020 Mar 7. J Cancer Res Clin Oncol. 2020. PMID: 32146565 Free PMC article.
-
Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.Circulation. 2024 Jul 23;150(4):302-316. doi: 10.1161/CIRCULATIONAHA.123.065304. Epub 2024 May 2. Circulation. 2024. PMID: 38695173 Free PMC article.
-
A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.Health Technol Assess. 2001;5(32):1-195. doi: 10.3310/hta5320. Health Technol Assess. 2001. PMID: 12065068
-
Gemcitabine-based chemotherapy for advanced biliary tract carcinomas.Cochrane Database Syst Rev. 2018 Apr 6;4(4):CD011746. doi: 10.1002/14651858.CD011746.pub2. Cochrane Database Syst Rev. 2018. PMID: 29624208 Free PMC article.
Cited by
-
Exploring RNA cargo in extracellular vesicles for pleural mesothelioma detection.BMC Cancer. 2025 Feb 7;25(1):212. doi: 10.1186/s12885-025-13617-y. BMC Cancer. 2025. PMID: 39920655 Free PMC article.
-
Potential roles of UCH family deubiquitinases in tumorigenesis and chemical inhibitors developed against them.Am J Cancer Res. 2024 Jun 15;14(6):2666-2694. doi: 10.62347/OEGE2648. eCollection 2024. Am J Cancer Res. 2024. PMID: 39005671 Free PMC article. Review.
-
Development and validation of nomograms to predict survival of neuroendocrine carcinoma in genitourinary system: A population-based retrospective study.PLoS One. 2024 Jun 5;19(6):e0303440. doi: 10.1371/journal.pone.0303440. eCollection 2024. PLoS One. 2024. PMID: 38837985 Free PMC article.
-
Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer.Cancer Cell. 2024 Jun 10;42(6):1086-1105.e13. doi: 10.1016/j.ccell.2024.05.003. Epub 2024 May 23. Cancer Cell. 2024. PMID: 38788720 Free PMC article.
-
The Pathogenesis of Nephrotic Syndrome: A Perspective from B Cells.Kidney Dis (Basel). 2024 Aug 29;10(6):531-544. doi: 10.1159/000540511. eCollection 2024 Dec. Kidney Dis (Basel). 2024. PMID: 39664337 Free PMC article. Review.
References
-
- Rindi G., Mete O., Uccella S., Basturk O., La Rosa S., Brosens L.A.A., Ezzat S., de Herder W.W., Klimstra D.S., Papotti M., Asa S.L. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr. Pathol. 2022;33:115–154. - PubMed
-
- van Meerbeeck J.P., Fennell D.A., De Ruysscher D.K.M. Small-cell lung cancer. Lancet. 2011;378:1741–1755. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous