PANoptosis-related HLTF promotes prostate cancer progression and serves as a potential therapeutic target

Abstract

Accumulating evidence indicates that pan-apoptosis plays a significant role in tumour progression, highlighting the importance of determining its relevance to tumour prognosis and treatment. This study aims to classify the molecular patterns of pan-apoptosis and explore the molecular and tumour microenvironment characteristics to predict the prognosis of prostate cancer. Prostate cancer samples were clustered into two subtypes based on the expression matrix of pan-apoptosis-related genes. Pan-apoptosis-related genes were identified using differential gene expression analysis. A novel model was developed incorporating the four core genes. Validation of the model was conducted through EdU assays, quantitative real-time PCR, and Western blotting. The pan-apoptosis model was successfully developed, demonstrating robust performance in prognostic prediction. Notably, the low PANS group exhibited higher TIDE scores than the high PANS group, suggesting a potentially less favorable response to immune checkpoint blockade therapy in the low-PANS population. Furthermore, our study revealed that HLTF was highly expressed in PRAD cell. Meanwhile, the function of HLTF in PRAD has been explored and the results showed the proliferation capacity of PRAD cell diminished following the knockdown of HLTF. Furthermore, our study uncovered a potential mechanistic link, suggesting that HLTF may regulate PANoptosis through the modulation of ZBP1-PANoptosome assembly. Molecular docking analysis identified several compounds and drugs that target HLTF. Among them, the small-molecule compound EGCG was found to interact with the HLTF protein and effectively reverse the enhanced proliferative capacity of prostate adenocarcinoma (PRAD) induced by HLTF overexpression. Our study investigated the mechanism of action of PANoptosis and emphasised its potential clinical applications. The PANoptosis model could accurately predict the prognosis of patients with PRAD and guide the treatment. HLTF could regulate the assembly of ZBP1-PANoptosome, thereby influencing the proliferation of prostate cancer cells. Additionally, EGCG and other HLTF-binding compounds merit further preclinical evaluation as potential therapeutic leads.