Ubiquitin C-terminal hydrolase L1 is a regulator of tumor growth and metastasis in double-negative prostate cancer

Shiqin Liu; Fernando Jose Garcia-Marques; Michelle Shen; Abel Bermudez; Sharon J Pitteri; Tanya Stoyanova

doi:10.62347/JNBR1463

Ubiquitin C-terminal hydrolase L1 is a regulator of tumor growth and metastasis in double-negative prostate cancer

Am J Clin Exp Urol. 2024 Oct 15;12(5):306-322. doi: 10.62347/JNBR1463. eCollection 2024.

Authors

Shiqin Liu¹, Fernando Jose Garcia-Marques², Michelle Shen¹, Abel Bermudez², Sharon J Pitteri², Tanya Stoyanova^{1

3}

Affiliations

¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles Los Angeles, CA, USA.
² Department of Radiology, Stanford University Palo Alto, CA, USA.
³ Department of Urology, University of California, Los Angeles Los Angeles, CA, USA.

Abstract

Prostate cancer is the second leading cause of cancer-related deaths among men worldwide. With heavy androgen deprivation therapies, prostate cancer may shift to androgen receptor negative and neuroendocrine negative subtype of castration resistant prostate cancer, defined as double-negative prostate cancer. Double-negative prostate cancer is associated with poor prognosis and disease mortality. The molecular mechanisms underlying the emergence of double-negative prostate cancer remain poorly understood. Here, we demonstrate that Ubiquitin C-Terminal Hydrolase L1 (UCH-L1), is negatively correlated with androgen receptor levels in prostate cancer patients. UCH-L1 plays a functional role in tumorigenesis and metastasis in double-negative prostate cancer. Knock-down of UCH-L1 decreases double-negative prostate cancer colony formation in vitro and tumor growth in vivo. Moreover, decrease of UCH-L1 significantly delays cell migration in vitro and spontaneous metastasis and metastatic colonization in vivo. Proteomic analysis revealed that mTORC1 signaling, androgen response signaling and MYC targets are the top three decreased pathways upon UCH-L1 decrease. Further, treatment with LDN-57444, a UCH-L1 small molecule inhibitor, impairs double-negative prostate cancer cell colony formation, migration in vitro, and metastatic colonization in vivo. Our study reveals that UCH-L1 is an important regulator of double-negative prostate cancer tumor growth and progression, providing a promising therapeutic target for this subtype of metastatic prostate cancer.

Keywords: UCH-L1; androgen receptor; metastasis; prostate cancer.