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.
Cell reports. Medicine. 2024 Jan 09 [Epub ahead of print]
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
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Radiology, Stanford University, Palo Alto, CA, USA., Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA., Department of Radiology, Stanford University, Palo Alto, CA, USA., Department of Pathology, Stanford University, Stanford, CA, USA., Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA., Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA., Department of Urology, University of Washington, Seattle, WA, USA., Department of Urology, Stanford University, Stanford, CA, USA., Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada., Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA., Department of Radiology, Stanford University, Palo Alto, CA, USA; Department of Electrical Engineering, Stanford University, Stanford, CA, USA., 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., Department of Urology, UT Health San Antonio, San Antonio, TX, USA., Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA., Department of Pathology, Duke University, Durham, NC, USA., 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: .