Jul 2026· Journal of Translational Medicine· 0 citations
Medicine
TL;DR
A novel non-canonical role of TRIM24 as a stabilizer of the p110 CUX1 oncoprotein by recruiting USP10 is revealed, presenting a promising therapeutic target for AML treatment.
Abstract
Background
Acute myeloid leukemia (AML) has a poor prognosis due to high chemoresistance and recurrence. TRIM24, an E3 ubiquitin ligase, is oncogenic in solid tumors, but its role in AML and regulation of the oncoprotein p110 CUX1 remain unclear.
Methods
We performed bioinformatic analysis to assess TRIM24 expression, prognosis, and protein-protein interactions. Functional studies used genetic manipulation and pharmacological inhibition in AML cells. Protein interactions were examined by Co-IP, IP-MS, and immunofluorescence. The stability and ubiquitination of p110 CUX1 were examined via CHX chase assays and ubiquitination profiling. The biological and therapeutic significance of the identified axis was validated using cell proliferation, apoptosis assays, drug sensitivity tests, and a CDX mouse model.
Results
TRIM24 is overexpressed in AML and predicts poor prognosis. TRIM24 promotes proliferation and inhibits apoptosis. Mechanistically, TRIM24 functions as a scaffold-like adaptor to recruit USP10 to deubiquitinate and stabilize p110 CUX1 via K48-linked ubiquitin chain cleavage. The TRIM24/USP10/p110 CUX1 axis activates the MAPK signaling pathway, with CUX1 regulating ERK transcription. TRIM24 overexpression enriches DNA repair pathways, conferring cytarabine resistance. Targeting TRIM24 genetically or with dTRIM24 sensitizes AML cells to cytarabine in vitro and in vivo.
Conclusion
Our study reveals a novel non-canonical role of TRIM24 as a stabilizer of the p110 CUX1 oncoprotein by recruiting USP10. This TRIM24/USP10/p110 CUX1 axis is critical for AML progression, clinical prognosis, and chemoresistance, presenting a promising therapeutic target for AML treatment.
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
Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo, and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.
Glioblastoma (GBM) is the most common malignant glioma, with a high recurrence rate and a poor prognosis. Deubiquitinating enzyme ubiquitin-specific peptidase 53 (USP53), known to enhance the stability of downstream proteins, exhibits distinct functions in different tumors. The function of USP53 in GBM progression remains unclear. Analysis of GSE104267 and GSE4290 datasets revealed significant USP53 upregulation in GBM tissues, a finding confirmed by TCGA data comparing GBM (n = 163) with normal brain tissues (n = 207). In univariate and multivariate cox regression analysis, USP53 was identified as an independent risk factor (univariate, hazard ratio (HR) =1.5357, p = 0.0229; multivariate, HR =1.4851, p = 0.0385) for GBM progression. Patients with high expression of USP53 had worse prognosis compared to those with low expression of USP53. Functionally, USP53 knockdown potently inhibited proliferation and induced apoptosis in LN229 and A172 cells in vitro and attenuated tumorigenicity of LN229 cells in vivo. Conversely, forced expression of USP53 had a carcinogenic effect. Mechanistically, USP53 targeted ALKB homolog 5 (ALKBH5) for deubiquitination, thereby stabilizing the protein and prolonging its half-life. Restoring ALKBH5 expression rescued the proliferative deficit in USP53-silenced LN229 cells. Telomerase catalytic subunit telomerase reverse transcriptase (TERT) was identified as a downstream effector of the USP53/ALKBH5 axis, where ALKBH5 upregulated TERT RNA expression by erasing m6A modifications at position 1989 bp on TERT mRNA. Collectively, those observations demonstrate that USP53/ALKBH5 axis drives GBM progression by targeting TERT, indicating that USP53/ALKBH5 axis may serve as a potential therapeutic target for GBM.
Guihong Li, T. Lei, Erpeng Liu et al.· Biochimica et Biophysica Act...· 0 citations
ABSTRACT Tripartite motif‐containing 59 (TRIM59) is an E3 ubiquitin ligase implicated in multiple malignancies, but its role in bladder cancer (BLCA) remains incompletely understood. In this study, we identified TRIM59 as a clinically relevant oncogenic driver in BLCA through integrated transcriptomic, clinical, and functional analyses. TRIM59 was significantly upregulated in BLCA tissues and cell lines, and high TRIM59 expression was associated with advanced stage, higher grade, recurrence, and poor prognosis. Functionally, TRIM59 promoted BLCA proliferation, cell‐cycle progression, migration, invasion, and metastatic colonization in vitro and in vivo. Mechanistically, TRIM59 directly interacted with PTRF/Cavin‐1 and induced its RING domain‐dependent K48‐linked polyubiquitination and proteasomal degradation. Additional mutagenesis analyses identified K98, K122, K152, and K317 as major ubiquitination sites on PTRF. In contrast to the oncogenic role of TRIM59, PTRF was downregulated in BLCA and exhibited tumor‐suppressive properties. PTRF restoration attenuated TRIM59‐driven proliferation, invasion, and epithelial‐mesenchymal transition, whereas PTRF depletion partially rescued the inhibitory effects of TRIM59 silencing. Further analyses showed that PTRF restrains AKT phosphorylation and suppresses MYC transcriptional activity, thereby limiting c‐Myc‐driven proliferative signaling. Collectively, these findings define a previously unrecognized TRIM59–PTRF–AKT/c‐Myc axis that drives BLCA progression and highlight TRIM59 as a potential prognostic biomarker and therapeutic target.
Junlin Gan, Xuesong Bai, Aijie Zhang et al.· Cancer Science· 0 citations
Cuproptosis, a recently identified form of regulated cell death, holds therapeutic promise in cancer. However, the mechanisms governing copper homeostasis and their impact on the immune landscape of clear cell renal cell carcinoma (ccRCC) remain poorly understood. A cuproptosis-related risk model was constructed to identify key prognostic factors. The role of ATP7B in ccRCC was validated using clinical cohorts, in vitro assays, and xenograft models. Mechanistic studies including Co-IP, ubiquitination assays, and Western blot were employed to elucidate the RNF186-p62-ATP7B axis. An autophagy-targeting chimera (ATAUTAC) was developed to evaluate its therapeutic and immunomodulatory potential. High ATP7B expression correlated with poor prognosis and immune evasion in ccRCC. We found that the E3 ligase RNF186 catalyzes K63-linked ubiquitination of ATP7B, driving its selective autophagic degradation via the receptor p62. In ccRCC, RNF186 downregulation leads to ATP7B accumulation, thereby limiting copper-induced proteotoxic stress. Our developed ATAUTAC effectively degraded ATP7B, disrupted mitochondrial TCA cycle metabolism, and induced canonical cuproptosis. Combining ATAUTAC with anti-PD-1 therapy significantly suppressed tumor growth and prolonged survival in vivo. Mechanistically, ATAUTAC-induced metabolic remodeling was accompanied by PD-L1 downregulation, enhanced CD8+ T-cell infiltration, pro-inflammatory cytokine release, and a shift of macrophages toward an M1-like anti-tumor phenotype. This study identifies the RNF186-p62-ATP7B axis as a critical regulator of copper homeostasis in ccRCC. Targeting ATP7B via ATAUTAC offers a potent strategy to induce cuproptosis and sensitize ccRCC to immunotherapy.
This study aims to investigate the biological function, molecular mechanisms, and impact on the tumor microenvironment of the ubiquitin-conjugating enzyme E2S (UBE2S) in the progression of kidney renal clear cell carcinoma (KIRC). Based on the TCGA and GEPIA databases, the relationship between UBE2S expression and patient prognosis was analyzed. Overexpression and knockdown models of UBE2S were established in Caki-1 and 786-O cell lines. Cell proliferation, apoptosis, and migration capabilities were assessed using CCK-8 assay, colony formation assay, flow cytometry, wound healing assay, and Transwell assay. Protein-protein interactions and expression regulatory mechanisms were validated by co-immunoprecipitation and Western blot. The proteasome inhibitor MG132 and ubiquitination assays were employed to investigate protein degradation mechanisms. Macrophage polarization was analyzed using a cell co-culture system, immunofluorescence staining, and Western blot. UBE2S is highly expressed in KIRC tissues and is associated with poor patient prognosis. Functional experiments demonstrate that UBE2S promotes KIRC cell proliferation and migration while inhibiting apoptosis. Mechanistically, UBE2S directly binds to and positively regulates CDC20 protein expression, and its oncogenic functions depend on CDC20. Furthermore, knockdown of UBE2S induces cuproptosis by activating FDX1 protein, thereby enhancing cellular sensitivity to cuproptosis inducers. UBE2S promotes FDX1 protein degradation via the ubiquitin-proteasome pathway. Additionally, tumor cells with high UBE2S expression promote macrophage polarization toward the M2 phenotype. UBE2S drives KIRC progression by regulating CDC20 expression and suppressing FDX1-mediated cuproptosis, thereby promoting tumor-associated macrophage polarization.
