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

• Published in: Cell reports. Medicine Vol. 5; no. 2; p. 101381
• Main Authors: Liu, Shiqin, Chai, Timothy, Garcia-Marques, Fernando, Yin, Qingqing, Hsu, En-Chi, Shen, Michelle, Shaw Toland, Angus Martin, Bermudez, Abel, Hartono, Alifiani B., Massey, Christopher F., Lee, Chung S., Zheng, Liwei, Baron, Maya, Denning, Caden J., Aslan, Merve, Nguyen, Holly M., Nolley, Rosalie, Zoubeidi, Amina, Das, Millie, Kunder, Christian A., Howitt, Brooke E., Soh, H. Tom, Weissman, Irving L., Liss, Michael A., Chin, Arnold I., Brooks, James D., Corey, Eva, Pitteri, Sharon J., Huang, Jiaoti, Stoyanova, Tanya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.02.2024; Elsevier
• Subjects: Carcinoma, Neuroendocrine - drug therapy; Carcinoma, Neuroendocrine - genetics; Humans; Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Male; Membrane Glycoproteins; neuroblastoma; neuroendocrine carcinomas; neuroendocrine prostate cancer; nuclear pore complex; small cell lung cancer; Small Cell Lung Carcinoma; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; UCHL1; neuroblastoma; nuclear pore complex; UCHL1; small cell lung cancer; neuroendocrine carcinomas; neuroendocrine prostate cancer
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101381

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. [Display omitted] •UCHL1 is a potential molecular indicator for neuroendocrine carcinomas•UCHL1 regulates neuroendocrine carcinoma tumor growth and metastasis•UCHL1 stabilizes POM121 and regulates POM121-driven E2F1 nuclear localization•UCHL1 is a therapeutic target for neuroendocrine carcinomas and neuroblastoma Liu et al. identify UCHL1 as a blood and tissue marker that is elevated across cancers with neuroendocrine features. These cancers are characterized by poor patient outcomes and lack effective treatments. UCHL1 inhibition exhibits anticancer effects in malignancies with neuroendocrine features, presenting a potent therapeutic strategy for these patients.