Deciphering USP8’s pivotal role in cancer - mechanisms, clinical insights and contrasts with its function in pituitary adenomas

Sep 23, 2026

Uploaded by hdkawk

The ubiquitin-proteasome system controls protein homeostasis through E1–E2–E3 ubiquitin ligases, while deubiquitinating enzymes (DUBs) reverse ubiquitination to sustain dynamic cellular balance. As a ubiquitin-specific protease, USP8 maintains substrate stability, and dysregulation drives initiation and progression of multiple malignancies by stabilizing oncogenic substrates that promote proliferation, invasion, and metastasis. USP8 mutations can also contribute to benign pituitary adenomas. This review compares its context-dependent mechanisms in cancer versus pituitary tumors, outlining clinical biomarker and unified therapeutic target value.

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Song et al. Journal of Translational Medicine (2026) 24:36 [https://doi.org/10.1186/s12967-025-07530-y](https://doi.org/10.1186/s12967-025-07530-y) Journal of Translational Medicine REVIEW Open Access Deciphering USP8’s pivotal role in cancer: mechanisms, clinical insights and contrasts with its function in pituitary adenomas Lifan Song 1†, Dexu Kong 1† and Lina Yang 1* Abstract Background The ubiquitin-proteasome system, orchestrated by E1-E2-E3 ubiquitinases, governs protein homeostasis, while deubiquitinating enzymes (DUBs) reverse this process to sustain cellular dynamics. As a key member of the ubiquitin-specific protease (USP) family, USP8 preserves substrate stability via its deubiquitinating activity, and its dysregulation drives the initiation and progression of diverse malignancies—by stabilizing oncogenic substrates to promote tumor proliferation, invasion, and metastasis—while its mutations can contribute to benign pituitary adenomas. Main body This review systematically summarizes USP8’s context-dependent roles in cancer biology, dissects the mechanistic basis for its divergent effects in cancers and pituitary adenoma, and highlights its clinical value as a differential biomarker and unifying therapeutic target across tumor types. Conclusion Ultimately, this work bridges gaps in cross-tumor USP8 research, provides a theoretical framework for precision tumor diagnosis, and offers novel insights to advance the development of USP-targeted therapies. Keywords Deubiquitinating enzyme, USP8, Cancer, Therapeutic target, Therapy resistance Introduction Protein ubiquitination, a pivotal post-translational modification governing protein turnover, signaling transduction, and cellular homeostasis, is tightly regulated by the sequential action of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases [1, 2]. This elaborate process is not irreversible, however—deubiquitination, mediated by deubiquitinating enzymes (DUBs), counteracts ubiquitination by †Lifan Song and Dexu Kong contributed equally to this work. *Correspondence: Lina Yang [Yanglina@qdu.edu.cn](Yanglina@qdu.edu.cn) 1School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, China cleaving covalent ubiquitin chains from substrate proteins. Beyond reversing ubiquitin modification, DUBs also recycle ubiquitin molecules, ensuring the dynamic equilibrium of the ubiquitin-proteasome system (UPS)—a balance critical for preventing aberrant protein accumulation or dysfunction that drives human pathologies [3–5]. Dysregulated DUB expression or activity has been linked to a spectrum of diseases, from neurodegenerative and autoimmune disorders to inflammatory conditions, with cancer emerging as one of the most clinically relevant contexts due to its profound impact on tumor initiation and progression [6, 7]. To date, over 100 DUBs have been identified in humans, categorized into six families based on structural motifs and catalytic mechanisms. Among these, the ubiquitin-specific proteases (USPs) family stands out as © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will

FAQs

What is USP8 and what role does it play in cells?

USP8 is a deubiquitinating enzyme within the ubiquitin-specific protease family. Its deubiquitinating activity helps preserve substrate stability and supports protein homeostasis dynamics.

How does USP8 dysregulation contribute to cancer development?

In cancers, USP8 dysregulation is linked to aberrant expression or activation that stabilizes oncogenic substrates and perturbs tumor-suppressive pathways, thereby promoting proliferation, invasion, and metastasis.

What is USP8’s relevance to pituitary adenomas and clinical use?

USP8 mutations can contribute to benign pituitary adenomas, particularly ACTH-secreting tumors related to Cushing’s disease. The review highlights USP8’s potential as a differential biomarker and a unifying therapeutic target across tumor types.

Sep 23, 2026

Uploaded by hdkawk