UCHL1 is a Potential Molecular Indicator and Therapeutic Target for Neuroendocrine Carcinomas

Overview

Journal Cell Rep Med

Publisher Cell Press

Specialties Biology
General Medicine

Date 2024 Jan 20

PMID 38244540

Authors

Shiqin Liu

Timothy Chai

Fernando Garcia-Marques

Qingqing Yin

En-Chi Hsu

Michelle Shen

Angus Martin Shaw Toland

Abel Bermudez

Alifiani B Hartono

Christopher F Massey

Chung S Lee

Liwei Zheng

Maya Baron

Caden J Denning

Merve Aslan

Holly M Nguyen

Rosalie Nolley

Amina Zoubeidi

Millie Das

Christian A Kunder

Brooke E Howitt

H Tom Soh

Irving L Weissman

Michael A Liss

Arnold I Chin

James D Brooks

Eva Corey

Sharon J Pitteri

Jiaoti Huang

Tanya Stoyanova

Affiliations

Soon will be listed here.

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.

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