Haoyue Sheng

PI3K-AKT signaling axis is often aberrantly activated in human cancers including prostate cancer, but the underlying mechanism of deregulation and tactics for effective targeting of this cancer relevant pathway remain poorly understood. Here, we demonstrate that KBTBD11 E3 ubiquitin ligase gene is frequently deleted in human prostate cancers and that KBTBD11 loss augments AKT phosphorylation in prostate cancer cells in culture and in patient samples. We show that KBTBD11 promotes lysine-27-chain polyubiquitination at lysine 8 and 14 on AKT and antagonizes ubiquitin K63 linkage-mediated polyubiquitination and phosphorylation of AKT. KBTBD11 deficiency drove prostate cancer cell growth in vitro and in vivo, but constituted as a therapeutic vulnerability to the selective AKT inhibitor in prostate cancer. Our study identifies lysine-27-chain polyubiquitination as an inhibitory mechanism of AKT activation and nominates KBTBD11 as an intrinsic upstream inhibitor of AKT. Our findings suggest that KBTBD11 deletion could be a biomarker to guide the use of the AKT inhibitors for the effective treatment of cancers such as prostate cancer.

Background: Cuproptosis is a newly identified form of cell death that is dependent on copper (Cu) ions, termed Cu-dependent cytotoxicity. This process is distinct from other forms of cell death such as apoptosis, necrosis, and ferroptosis. The accumulation of copper is known to play a significant role in various biological processes, including angiogenesis (the formation of new blood vessels) and metastasis (the spread of cancer cells to different parts of the body). These processes are crucial for tumor growth and progression, indicating that copper and the cuproptosis-related genes (CPRGs) might be indispensable in the context of cancer development and progression. Given this background, we aimed to explore the relationship between CPRGs and both prognostic predictions and tumor microenvironment (TME) infiltration in bladder cancer (BLCA). Methods: For this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify CPRGs and subsequently divided BLCA patients into three distinct molecular clusters based on these genes. To assess the proportions of various immune cell types within the TME, we employed single-sample gene set enrichment analysis (ssGSEA) and the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) method. These computational techniques allowed us to quantify the infiltration of different immune cells, providing insights into the immune landscape of the tumors. Furthermore, we developed a risk score model using CPRGs to predict the survival prospects of BLCA patients. Results: Our analysis identified three molecular clusters of BLCA patients, each exhibiting unique clinical features and patterns of TME infiltration. Among these clusters, cluster 1 was associated with a poor prognosis. Interestingly, this cluster also showed significant infiltration of activated CD4⁺ (ssGSEA P+ T (ssGSEA P+ and CD8⁺ T cells. This indicates that the cuproptosis-based risk model has a robust ability to predict patient prognosis and can guide immunotherapy decisions. Conclusions: Our study sheds light on the biological functions of CPRGs within the TME of BLCA and their correlations with clinical parameters and patient prognosis. The identification of distinct molecular clusters with varying prognoses and immune cell infiltrations highlights the heterogeneity of BLCA and underscores the potential of CPRGs as biomarkers for prognosis and therapeutic targets. These findings offer new perspectives for the development of immunotherapeutic strategies in the treatment of BLCA patients, potentially leading to more personalized and effective cancer therapies.

Androgen receptor–positive prostate cancer (PCa) and estrogen receptor–positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.

Increasing evidence demonstrated that noncoding RNA is abnormally expressed in cancer tissues and serves a vital role in tumorigenesis, tumor development, and metastasis. The aim of the present study was to determine an lncRNA signature in order to predict the overall survival (OS) of patients with muscle-invasive bladder cancer (MIBC). A total of 246 patients with pathologically confirmed MIBC in The Cancer Genome Atlas (TCGA) dataset were recruited and included in the present study. We choose patients who have smoked less (including never smoking) or more than 15 years. A total of 44 differentially expressed lncRNAs were identified with a fold change larger than 1.5 and a value < 0.05 through the limma package. Subsequently, a comparison between patients with no tobacco smoke exposure for 15 years was performed by using the matchIt package. Among the 44 differentially expressed lncRNAs, 5 lncRNAs were identified to be significantly associated with OS. Based on the characteristic risk scores of these 5 lncRNAs, patients were divided into low-risk and high-risk groups and exhibited significant differences in OS. Multivariate Cox regression analysis demonstrated that the 5-lncRNA signature was independent of age, tumor-node metastasis (TNM) staging, lymphatic node status, and adjuvant postoperative radiotherapy. In the present study, a novel 5-lncRNA signature was developed and was demonstrated to be useful in predicting the survival of patients with MIBC. If validated, this lncRNA signature may assist in the selection of a high-risk subpopulation that requires more aggressive therapeutic intervention. The risk scores involved in several associated pathways were identified using gene set enrichment analysis (GSEA). However, the clinical implications and mechanism of these 5 lncRNAs require further investigation.