Lactylation-driven transcriptional activation of FBXO33 promotes gallbladder cancer metastasis by regulating p53 polyubiquitination

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 28, 2025

Abstract Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract and often prone to early distant metastasis. However, mechanisms underlying GBC’s invasive metastasis remain unclear. This study identified that F-box only protein 33 (FBXO33) expression significantly elevated in GBC negatively associated with patient prognosis. In vivo vitro experiments demonstrated knockdown FBXO33 inhibits epithelial-mesenchymal transition (EMT) progression GBC, while overexpression promotes EMT progression. Mechanistically, regulates by modulating polyubiquitination p53 at K291 K292. Moreover, upregulation driven transcriptional regulation mediated Yin Yang-1 (YY1). The lactylation modification YY1 K183 was found be essential for activation FBXO33. These findings underscore role lactylation-driven FBXO33-p53 axis promoting GBC.

Language: Английский

Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(6)

Published: March 20, 2025

Abstract Transcription factors orchestrate gene expression through a myriad of complex mechanisms, encompassing collaborations with other transcription and the formation multimeric complexes. The chromatin-binding protein SAMD1 [sterile alpha motif (SAM) domain-containing 1] binds to unmethylated CpG-rich DNA utilizing its N-terminal winged-helix (WH) domain. Additionally, C-terminal SAM domain, which mediates interactions itself L3MBTL3, is crucial for chromatin binding. precise role domain in this process remains unclear. Using structural analyses, we elucidated distinct homopolymerization modes within domains L3MBTL3 SAMD1, alongside their heterodimerization architecture. Interestingly, necessitates not only WH but also proline/alanine-rich intrinsically disordered region (IDR) efficient IDR essential ability form large polymers, functionality determined by integrity rather than specific sequence. Mutagenesis studies underscore critical arginines polymerization, binding, biological function SAMD1. These findings propose model structured unstructured regions cooperate coordinated fashion facilitate This work provides new insights into diverse mechanisms employ interact regulate expression.

Language: Английский

Development and validation of hierarchical signature for precision individualized therapy based on the landscape associated with necroptosis in clear cell renal cell carcinoma

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 4, 2025

Background Increasing evidence is showing that necroptosis has unique clinical significance in the occurrence and development of multiple diseases. Here, we systematically evaluate role clear cell renal carcinoma (ccRCC) analyze its regulatory patterns. Methods First, evaluated expression enrichment necroptotic factors ccRCC using gene set analysis (GSEA) survival profile from The Cancer Genome Atlas (TCGA) to demonstrate overall mutation pathway genes. Then, used unsupervised clustering divide samples into two subtypes related with significant differences (OS) subsequently detected differentially expressed genes (DEGs) between them. Based on this, constructed scoring system (NSS), which also performed outstandingly hierarchical data. Finally, analyzed association NSS parameters, immune infiltration, efficacy immunotherapy containing checkpoint inhibitors (ICIs), suggested potential therapeutic strategies. Results We screened 97 necroptosis-related demonstrated they were dysregulated ccRCC. Using Cox least absolute shrinkage selection operator (LASSO) regression, a prognostic prediction signature seven was built. Receiver operating characteristic (ROC) curves Kaplan–Meier (KM) analyses both showed model accurate, univariate/multivariate as an independent factor, higher risk score, poorer outcome. Furthermore, predicted scores based observably associated infiltration specific In addition, score could potentially predict patients’ responsiveness different chemotherapy regimens. Specifically, Nivolumab more effective for patients scores. Conclusion can accurately prognosis further provide clues targeted, individualized therapy.

Language: Английский