YL064 is established 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.
Abstract
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.
Lung adenocarcinoma (LUAD) remains a significant clinical challenge due to its high rate of recurrence, and the molecular mechanisms driving its malignant progression remain incompletely understood. The functional role of SH3PX1 in LUAD was assessed using in vitro assays (CCK-8, colony formation, EdU, cell cycle, and metabolic assays) as well as in vivo xenograft models. Bioinformatic analysis revealed that SH3PX1 is upregulated in LUAD, and its elevated expression is associated with poor patient prognosis. In LUAD cell lines, overexpression of SH3PX1 promoted cell proliferation and glycolysis, whereas SH3PX1 knockdown produced the opposite effects. Moreover, SH3PX1 enhanced tumor growth in vivo. Mechanistically, SH3PX1 was identified to interact with GALNT2, a key enzyme responsible for initiating protein O-glycosylation. We further demonstrated that the stability of SH3PX1 was regulated by GALNT2-mediated O-glycosylation at serine 92 (S92). Additionally, the pro-tumorigenic effects of GALNT2 on LUAD cell malignancy were suppressed upon SH3PX1 knockdown, indicating that SH3PX1 serves as a downstream mediator of GALNT2 in LUAD pathogenesis. Collectively, these findings provide that SH3PX1 acts as a regulator of LUAD malignancy through GALNT2-mediated O-glycosylation and stabilization, suggesting that targeting SH3PX1 may represent a potential therapeutic strategy for LUAD.
Siyao Wang, Yingqi Tang, Ye-Gang Ma et al.· Cellular Signalling· 0 citations
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, highlighting the urgent need for novel diagnostic and therapeutic targets. In this study, through integrated proteomic profiling, we identify AP4M1 as a potential therapeutic vulnerability for HCC and characterize its upstream regulatory and downstream effector mechanisms. We show that AP4M1 is markedly upregulated in HCC, correlates with unfavorable prognosis, and is functionally involved in driving HCC progression. Mechanistically, the deubiquitinase USP15 stabilizes AP4M1 by removing K11- and K48-linked polyubiquitin chains at lysine 163 (K163). Additionally, MINK1-mediated phosphorylation of AP4M1 at threonine 69 (T69) is critical for its interaction with GPX4. Through upregulating GPX4, AP4M1 reduces intracellular lipid peroxidation, thereby suppressing ferroptosis and facilitating HCC tumorigenesis and progression. Importantly, combined treatment with the USP15 inhibitor USP15-IN-1 and the GPX4 inhibitor RSL3 exhibits potent anti-tumor efficacy in both in vitro and in vivo models, underscoring the therapeutic potential of targeting the AP4M1 axis in HCC. Collectively, this study delineates the USP15/AP4M1/MINK1/GPX4 axis as a previously unrecognized ferroptosis-suppressive pathway that promotes HCC progression, providing a critical theoretical basis for AP4M1-targeted therapeutic strategies in HCC.
Yuan-Hao Peng, K. Kang, Xuanxuan Li et al.· Cancer Letters· 0 citations
Colorectal cancer (CRC) pathogenesis involves complex alterations in tumor suppressor genes and oncogenes. Although ubiquitin-mediated proteolysis represents a well-established regulatory mechanism, the functions of many E3 ubiquitin ligases in CRC remain poorly characterized. In this study, we identified the Rab effector SYTL4 (Synaptotagmin Like 4) as a potential uncharacterized E3 ubiquitin ligase with tumor-suppressive properties in colorectal cancer. Integrated analysis of TCGA and CPTAC datasets, validated with our clinical samples, demonstrated that lower SYTL4 protein abundance correlates strongly with unfavorable clinical outcomes of CRC patients. Functional analyses revealed that SYTL4 overexpression potently suppresses CRC cell proliferation, clonogenicity, and xenograft tumor growth. We identified SEC31B, a structural subunit of COPII vesicle coats, as the primary downstream mediator governed by SYTL4. We further showed that SYTL4 directly interacts with SEC31B and functions as an E3 ubiquitin ligase to trigger K48-type polyubiquitination of SEC31B and subsequent proteasome-dependent degradation. SEC31B exhibited intrinsic oncogenic properties, and its overexpression counteracted the tumor-suppressive effects of SYTL4. Collectively, our results delineate the SYTL4-SEC31B axis as a pivotal regulatory pathway in CRC tumorigenesis, which provides a promising candidate therapeutic target for colorectal cancer clinical intervention.
Jin-lei Li, Xiaodong Zhang, Hongyan Li et al.· Biochemical and Biophysical...· 0 citations
The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in triple-negative breast cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.
Yu-Zhan Li, Yaxun Guo, Dazhao Mi et al.· European journal of medicina...· 0 citations
A dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction between UBE2M and DCN1, which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs) and histone deacetylase (HDAC) activity is developed.
Tao Zheng, Yigui Li, Yunyuan Huang et al.· Journal of Medicinal Chemist...· 0 citations
Summary Hepatocellular carcinoma (HCC) has a poor prognosis, necessitating therapeutic targets, while the role of ubiquitin-specific protease 3 (USP3) in HCC remains unclear. This study aimed to elucidate the function of the deubiquitinating enzyme USP3 in HCC. USP3 was found to be highly expressed in HCC tissues and associated with poor prognosis. Functional assays in cells and animal models confirmed that USP3 promotes tumor proliferation, migration, and invasion. Mechanistically, USP3 directly binds to yes1-associated transcriptional regulator (YAP) via its ubiquitin C-terminal hydrolase (UCH) domain interacting with YAP’s WW domain, removing K11/K48-linked polyubiquitin chains to stabilize the YAP protein. The screening results showed that the pan-deubiquitinating enzyme (DUB) inhibitor PR-619 could inhibit USP3 activity to a certain extent and significantly suppress the growth and metastasis of HCC. Notably, YAP overexpression partially reversed this inhibition. In conclusion, USP3 drives HCC progression by deubiquitinating and stabilizing YAP, and PR-619 demonstrates anti-tumor efficacy, establishing USP3 as a potential therapeutic target for HCC.
Yuan-Hao Peng, H. Nie, Xuanxuan Li et al.· iScience· 0 citations
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