UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

UCHL1 neuroblastoma neuroendocrine carcinomas neuroendocrine prostate cancer nuclear pore complex small cell lung cancer

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
09 Jan 2024
Historique:
received: 23 03 2023
revised: 18 09 2023
accepted: 19 12 2023
medline: 21 1 2024
pubmed: 21 1 2024
entrez: 20 1 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.xcrm.2023.101381 PMID: 38244540
pubmed: 38244540
pii: S2666-3791(23)00610-9
doi: 10.1016/j.xcrm.2023.101381
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101381

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Shiqin Liu (S)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Radiology, Stanford University, Palo Alto, CA, USA.

Timothy Chai (T)

Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Fernando Garcia-Marques (F)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Qingqing Yin (Q)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

En-Chi Hsu (EC)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Michelle Shen (M)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Radiology, Stanford University, Palo Alto, CA, USA.

Angus Martin Shaw Toland (AM)

Department of Pathology, Stanford University, Stanford, CA, USA.

Abel Bermudez (A)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Alifiani B Hartono (AB)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.

Christopher F Massey (CF)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.

Chung S Lee (CS)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.

Liwei Zheng (L)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Maya Baron (M)

Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.

Caden J Denning (CJ)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Merve Aslan (M)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Holly M Nguyen (HM)

Department of Urology, University of Washington, Seattle, WA, USA.

Rosalie Nolley (R)

Department of Urology, Stanford University, Stanford, CA, USA.

Amina Zoubeidi (A)

Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.

Millie Das (M)

Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA.

Christian A Kunder (CA)

Department of Pathology, Stanford University, Stanford, CA, USA.

Brooke E Howitt (BE)

Department of Pathology, Stanford University, Stanford, CA, USA.

H Tom Soh (HT)

Department of Radiology, Stanford University, Palo Alto, CA, USA; Department of Electrical Engineering, Stanford University, Stanford, CA, USA.

Irving L Weissman (IL)

Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA, USA.

Michael A Liss (MA)

Department of Urology, UT Health San Antonio, San Antonio, TX, USA.

Arnold I Chin (AI)

Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA.

James D Brooks (JD)

Department of Urology, Stanford University, Stanford, CA, USA.

Eva Corey (E)

Department of Urology, University of Washington, Seattle, WA, USA.

Sharon J Pitteri (SJ)

Department of Radiology, Stanford University, Palo Alto, CA, USA.

Jiaoti Huang (J)

Department of Pathology, Duke University, Durham, NC, USA.

Tanya Stoyanova (T)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Radiology, Stanford University, Palo Alto, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: tstoyanova@mednet.ucla.edu.

Classifications MeSH