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Abstract Neuroendocrine carcinomas, such as neuroendocrine prostate cancer (NEPC), small cell lung cancer (SCLC), and neuroblastoma, share common histological features, including expression of neuroendocrine markers, rapid relapse after treatment, and poor prognosis. Due to the poor clinical outcome of patients with neuroendocrine carcinomas, there is a critical need to identify new drivers, therapeutic targets, and effective therapeutic strategies for these malignancies. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a protease that has a dual function in regulating protein stability. We demonstrated that UCHL1 is significantly elevated in tissues from patients with NEPC, SCLC, and neuroblastoma. 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 key transcriptional factors, E2F1 and c-MYC. Conversely, UCHL1 binds p53 and promotes p53 degradation. Importantly, treatment with UCHL1 inhibitors significantly reduces tumor growth and metastasis of neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, halts tumor growth in pre-clinical settings. Our study reveals new mechanisms of UCHL1 function in neuroendocrine carcinomas tumorigenesis and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosis and monitoring treatment responses in neuroendocrine carcinomas. Citation Format: Shiqin Liu, Timothy Chai, Fernando Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Toland, Abel Bermudez, Alifiani B. Hartono, Christopher F. Massey, Chung S. Lee, Liwei Zheng, Maya Baron, Caden J. Denning, Merve Aslan, Holly Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian Kunder, Brooke Howitt, H Tom Soh, Irving L. Weissman, Michael A. Liss, Arnold I. Chin, James D. Brooks, Eva Corey, Sharon Pitteri, Jiaoti Huang, Tanya Ivanova Stoyanova. UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6574.
Liu et al. (Fri,) studied this question.