ATXN3 has recently emerged as a pro-oncogenic deubiquitinating enzyme (DUB) involved in the progression of multiple cancers, including breast and prostate cancer. However, the therapeutic potential of targeting ATXN3 remains largely unexplored due to the lack of effective inhibitors. In this study, we performed an Ub-AMC-based high-throughput screening assay using full-length ATXN3 and identified YL064, a derivative of the natural product sinomenine isolated from
Sinomenium acutum
, as a novel ATXN3 inhibitor. Direct interaction between YL064 and ATXN3 was confirmed by thermal shift assay, cellular thermal shift assay, surface plasmon resonance, and molecular docking analysis. Functionally, YL064 suppressed cancer cell proliferation, induced cell-cycle arrest, and reduced metastatic potential. Mechanistically, YL064 inhibited ATXN3 deubiquitinating activity and promoted the ubiquitination and proteasomal degradation of ATXN3 substrates, including KLF4 and YAP. Furthermore, YL064 significantly inhibited tumor growth in an orthotopic breast cancer model in vivo. Collectively, our findings establish YL064 as a promising ATXN3 inhibitor that targets the ubiquitin-proteasome pathway to exert anti-tumor effects, highlighting its potential as a novel therapeutic agent for ATXN3-driven cancers.
Zhenge Zhang, Wenhui Bai, Yayue Tan et al.· Cell Death & Disease· 0 citations
Ubiquitin-specific protease 2 (USP2), a pivotal member of the deubiquitinating enzyme family, has emerged as a critical but context-dependent regulator in cancer, exhibiting paradoxical tumor-suppressive and oncogenic functions. This duality is governed by its ability to stabilize specific substrate proteins, thereby modulating central signaling hubs including the p53, Wnt/β-catenin, PI3K/Akt, and cell cycle networks. Through these axes, USP2 profoundly influences hallmark cancer phenotypes such as sustained proliferation, metabolic reprogramming, metastatic progression, immune evasion, and therapy resistance. This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword. We detail how specific interactions between USP2 and its substrates dictate its pro-tumorigenic or anti-tumorigenic outcomes, depending on the tissue and microenvironment. Furthermore, we comprehensively evaluate the landscape of emerging USP2 inhibitors, discussing their therapeutic potential and the significant challenges posed by USP2's functional duality, substrate promiscuity, and isoform diversity. Targeting USP2 presents a promising yet intricate avenue for cancer therapy, necessitating future research focused on patient stratification, combination strategies, and the development of context-specific inhibitors.
Peng Hao, Jiale Wan, Zhangyu Guo et al.· Biochimica et biophysica act...· 0 citations