HUWE1 (HECT UBA And WWE Domain Containing E3 Ubiquitin Protein Ligase 1)

Our findings positioned kitasamycin as a promising adjunct to immunotherapy for cancer patients requiring concurrent antibiotic therapy. Abbreviations: FTH1: ferritin heavy chain 1; ICB: immune checkpoint blockade; IFNG: interferon gamma; mIHC: multiplex immunohistochemistry; scRNA-seq: single-cell RNA sequencing.

Depletion or mutation of the E3 ligases in cells and human cancer samples increases A3-driven genome mutagenesis. Our findings reveal that UBR4, UBR5, and HUWE1 are crucial factors in a ubiquitination cascade that maintains human genome stability.

To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.

Natural compounds (neferine, ajoene, baicalein, isoliensinine, curcumin analogs) and synthetic drugs (5-FU, oxaliplatin, irinotecan, norcantharidin, cordycepin) modulate EMT and trigger ferroptosis, cuproptosis, paraptosis, and autophagy...Simultaneous targeting of EMT, CR-CSC maintenance, and chemoresistance using multifunctional natural and synthetic agents represents a promising strategy in CRC therapy. Induction of alternative cell death pathways may improve response, minimize relapse, and enable combinatorial regimens for resistant tumors.

The CSC-defective traits in DDB1-deficient CRC cells were rescued by p53 deficiency but not by its overexpression, indicating that the CUL4A-DDB1-mediated regulation of p53 stability may control cancer stem-like properties in CRC. In summary, our findings emphasize DDB1 as a key regulator of colorectal cancer stemness and p53 stability through its O-GlcNAcylation at Ser-764, which enhances the E3 ligase activity of the CUL4-DDB1 complex.

Their prognostic value remained significant after adjusting for copy number alterations and transcriptomic subtypes. A 4-feature model integrating these two promoter activities with two clinical variables (Tumor size, Ki67 index) achieved an AUROC of 0.73 and improved patient risk stratification, with a Net Reclassification Improvement (NRI) of 0.40-0.48 over the clinical-only model, underscoring the potential of promoter activity as a biomarker in TNBC.

In conclusion, this study uncovers a previously unrecognized role of HUWE1 in regulating Wnt/β-catenin signaling and its impact on CRC. These insights may aid in identifying colorectal CSCs and developing targeted therapeutic strategies.

NDUFS8 is a mitochondrial regulator that promotes HCC progression through metabolic activation and is post-translationally modified by HUWE1. Targeting NDUFS8 or its regulatory axis may represent a promising therapeutic strategy for HCC.

Our analysis highlights the potential of PCLO as a candidate gene for enhancing immune cell infiltration and activating immune responses in tumors. The peptides SISRFTLEK (PCLOL4169F) and LSEAGHFFY (PCLOA3000S) are promising targets for tumor vaccines.

Together, our findings demonstrate that the lncRNA HOTTIP, a novel effector of the Hh pathway, drives colorectal cancer progression by promoting HUWE1-dependent ubiquitin‒proteasome degradation of p53. These findings reveal critical roles of the Hh-HOTTIP-p53 signaling axis in colorectal cancer progression and suggest a potential therapeutic target for colorectal cancer.

HDAC6 CD1 also regulated the protein levels of E3 ligase UBR5. These studies document the interplay between protein deacetylation and degradation by HDAC6 CD1, which is consistent with a model where HDAC6 CD1-mediated deacetylation influences protein degradation via E3 ligases.

BIRC6 mono-ubiquitinates TRIM52, with subsequent extension by UBR4/KCMF1. These findings suggest a role for TRIM52 in maintaining genome integrity, and regulation of its own abundance through multi-ligase degradation.