NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10.

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.

Branched-chain keto-acid dehydrogenase kinase regulates vascular permeability and angiogenesis to facilitate tumor metastasis in renal cell carcinoma.

Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC.

Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development.

The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. Video Abstract.

HDAC3 Contributes to Ischemic Stroke by Regulating Interferon Pathway.

BACKGROUND: The inflammation and immune response contribute to ischemic stroke pathology. Damaged brain cells release inflammatory substances to activate the immune system in the acute phase of stroke, including altering the interferon signaling pathway. However, the involvement of histone deacetylation in stroke remains unclear. METHODS: To investigate whether histone deacetylation modulation could regulate the interferon signaling pathway and mediate the pathogenic changes after stroke, the middle cerebral artery occlusion (MCAO) mouse model was treated with histone deacetylase 3 (HDAC3) inhibitor and RGFP966. Additionally, a series of approaches, including middle cerebral artery occlusion (MCAO), real-time polymerase chain reaction (PCR), western blot, 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavioral experiments, and confocal imaging were utilized. RESULTS: It is observed that RGFP966 pretreatment could lead to better outcomes in the MCAO mouse model, including the decrease of infarction volumes, the amelioration of post-stroke anxiety-like behavior, and the relief of inflammatory responses. Furthermore, we found that RGFP966 could counteract the hyperactivation of the interferon signaling pathway and the excessive expression of Z-DNA Binding Protein 1 (ZBP1) in microglia. CONCLUSIONS: We demonstrated a novel mechanism that HDAC3 inhibition could ameliorate the pathological injury after ischemic stroke by downregulating the ZBP1/phosphorylated Interferon Regulatory Factor 3 (p-IRF3) pathway. Thus, these data provide a new promising target for therapies for ischemic stroke.

Prognostic and Immunological Role of STK38 across Cancers: Friend or Foe?

Although STK38 (serine-threonine kinase 38) has been proven to play an important role in cancer initiation and progression based on a series of cell and animal experiments, no systemic assessment of STK38 across human cancers is available. We firstly performed a pan-cancer analysis of STK38 in this study. The expression level of STK38 was significantly different between tumor and normal tissues in 15 types of cancers. Meanwhile, a prognosis analysis showed that a distinct relationship existed between STK38 expression and the clinical prognosis of cancer patients. Furthermore, the expression of STK38 was related to the infiltration of immune cells, such as NK cells, memory CD4+ T cells, mast cells and cancer-associated fibroblasts in a few cancers. There were three immune-associated signaling pathways involved in KEGG analysis of STK38. In general, STK38 shows a significant prognostic value in different cancers and is closely associated with cancer immunity.

Discovery of a small-molecule NDR1 agonist for prostate cancer therapy.

Prostatic cancer (PCa) is a common malignant neoplasm in men worldwide. Most patients develop castration-resistant prostate cancer (CRPC) after treatment with androgen deprivation therapy (ADT), usually resulting in death. Therefore, investigating new therapeutic targets and drugs for PCa patients is urgently needed. Nuclear Dbf2-related kinase 1 (NDR1), also known as STK38, is a serine/threonine kinase in the NDR/LATS kinase family that plays a critical role in cellular processes, including immunity, inflammation, metastasis, and tumorigenesis. It was reported that NDR1 inhibited the metastasis of prostate cancer cells by suppressing epithelial-mesenchymal transition (EMT), and decreased NDR1 expression might lead to a poorer prognosis, suggesting the enormous potential of NDR1 in antitumorigenesis. In this study, we characterized a small-molecule agonist named aNDR1, which specifically bound to NDR1 and potently promoted NDR1 expression, enzymatic activity and phosphorylation. aNDR1 exhibited drug-like properties, such as favorable stability, plasma protein binding capacity, cell membrane permeability, and PCa cell-specific inhibition, while having no obvious effect on normal prostate cells. Meanwhile, aNDR1 exhibited good antitumor activity both in vitro and in vivo. aNDR1 inhibited proliferation and migration of PCa cells and promoted apoptosis of PCa cells in vitro. We further found that aNDR1 inhibited subcutaneous tumors and lung metastatic nodules in vivo, with no obvious toxicity to the body. In summary, our study presents a potential small-molecule lead compound that targets NDR1 for clinical therapy of PCa patients.

Establishment and validation of a novel anoikis-related prognostic signature of clear cell renal cell carcinoma.

Background: Despite progression in its treatment, the clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) remains not ideal. Anoikis is a unique form of programmed apoptosis, owing to insufficient cell-matrix interactions. Anoikis plays a crucial role in tumor migration and invasion, and tumor cells could protect themselves through the capacity of anoikis resistance. Methods: Anoikis-related genes (ARGs) were obtained from Genecards and Harmonizome portals. The ARGs related to ccRCC prognosis were identified through univariate Cox regression analysis, then we utilized these ARGs to construct a novel prognostic model for ccRCC patients. Moreover, we explored the expression profile of ARGs in ccRCC using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. We also conducted Real-Time Polymerase Chain Reaction (RT-PCR) to probe ARGs expression of the risk score. Finally, we performed correlation analysis between ARGs and tumor immune microenvironment. Results: We identified 17 ARGs associated with ccRCC survival, from which 7 genes were chosen to construct a prognostic model. The prognostic model was verified as an independent prognostic indicator. The expression of most ARGs was higher in ccRCC samples. These ARGs were closely correlated with immune cell infiltration and immune checkpoint members, and had independent prognostic value respectively. Functional enrichment analysis demonstrated that these ARGs were significantly associated with multiple types of malignances. Conclusion: The prognostic signature was identified to be highly efficient in predicting ccRCC prognosis, and these ARGs were closely related to tumor microenvironment.

BCKDK regulates breast cancer cell adhesion and tumor metastasis by inhibiting TRIM21 ubiquitinate talin1.

Breast cancer is the most common malignant cancer in women worldwide. Cancer metastasis is the major cause of cancer-related deaths. BCKDK is associated with various diseases, including proliferation, migration, and invasion in multiple types of human cancers. However, the relevance of BCKDK to the development and progression of breast cancers and its function is unclear. This study found that BCKDK was overexpressed in breast cancer, associated with poor prognosis, and implicated in tumor metastasis. The downregulation of BCKDK expression inhibited the migration of human breast cancer cells in vitro and diminished lung metastasis in vivo. BCKDK perturbed the cadherin-catenin complex at the adherens junctions (AJs) and assembled focal adhesions (FAs) onto the extracellular matrix, thereby promoting the directed migration of breast cancer cells. We observed that BCKDK acted as a conserved regulator of the ubiquitination of cytoskeletal protein talin1 and the activation of the FAK/MAPK pathway. Further studies revealed that BCKDK inhibited the binding of talin1 to E3 ubiquitin ligase-TRIM21, leading to the decreased ubiquitination/degradation of talin1. In conclusion, identifying BCKDK as a biomarker for breast cancer metastasis facilitated further research on diagnostic biomarkers. Elucidating the mechanism by which BCKDK exerted its biological effect could provide a new theoretical basis for developing new markers for breast cancer metastasis and contribute to developing new therapies for the clinical treatment of breast cancer patients.

TOPK mediates immune evasion of renal cell carcinoma via upregulating the expression of PD-L1.

Although anti-PD-L1 therapy has been used in the clinical treatment of renal cell carcinoma (RCC), a proportion of patients are not sensitive to it, which may be attributed to the heterogeneity of PD-L1 expression. Here, we demonstrated that high TOPK (T-LAK cell-originated Protein Kinase) expression in RCC promoted PD-L1 expression by activating ERK2 and TGF-ß/Smad pathways. TOPK was positively correlated with PD-L1 expression levels in RCC. Meanwhile, TOPK significantly inhibited the infiltration and function of CD8+ T cells and promoted the immune escape of RCC. Moreover, inhibition of TOPK significantly enhanced CD8+ T cell infiltration, promoted CD8+ T cell activation, enhanced anti-PD-L1 therapeutic efficacy, and synergistically enhanced anti-RCC immune response. In conclusion, this study proposes a new PD-L1 regulatory mechanism that is expected to improve the effectiveness of immunotherapy for RCC.

Insights into prognosis and immune infiltration of cuproptosis-related genes in breast cancer.

Introduction: Breast cancer (BC) has been ranking first in incidence and the leading cause of death among female cancers worldwide based on the latest report. Regulated cell death (RCD) plays a significant role in tumor initiation and provides an important target of cancer treatment. Cuproptosis, a novel form of RCD, is ignited by mitochondrial stress, particularly the lipoylated mitochondrial enzymes aggregation. However, the role of cuproptosis-related genes (CRGs) in tumor generation and progression remains unclear. Methods: In this study, the mRNA expression data of CRGs in BC and normal breast tissue were extracted from TCGA database, and protein expression patterns of these CRGs were analyzed using UALCAN. The prognostic values of CRGs in BC were explored by using KaplanMeier plotter and Cox regression analysis. Genetic mutations profiles were evaluated using the cBioPortal database. Meanwhile, we utilized CIBERSORT and TIMER 2.0 database to perform the correlation analysis between CRGs and immune cell infiltration. Results: Our results indicated that CRGs expression is significantly different in BC and normal breast tissues. Then we found that upregulated PDHA1 expression was associated with worse endpoint of BC. Moreover, we also performed immune infiltration analysis of CRGs, and demonstrated that PDHA1 expression was closely related to the infiltration levels of CD4+ memory T cell, macrophage M0 and M1 cell and mast cell in BC. Conclusions: Our results demonstrated the prognostic and immunogenetic values of PDHA1 in BC. Therefore, PDHA1 can be an independent prognostic biomarker and potential target for immunotherapy of BC.

Identification and Validation of a Novel Ferroptotic Prognostic Genes-Based Signature of Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC), as one of the primary urological malignant neoplasms, shows poor survival, and the leading pathological type of RCC is clear cell RCC (ccRCC). Differing from other cell deaths (such as apoptosis, necroptosis, pyroptosis, and autophagy), ferroptosis is characterized by iron-dependence, polyunsaturated fatty acid oxidization, and lipid peroxide accumulation. We analyzed the ferroptosis database (FerrDb V2), Gene Expression Omnibus database, The Cancer Genome Atlas database, and the ArrayExpress database. Nine genes that were differentially expressed and related to prognosis were involved in the ferroptotic prognostic model via the least absolute shrinkage and selection operator Cox regression analysis, which was established in ccRCC patients from the kidney renal clear cell carcinoma (KIRC) cohort in TCGA database, and validated in ccRCC patients from the E-MTAB-1980 cohort in the ArrayExpress database. The signature could be an independent prognostic factor for ccRCC, and high-risk patients showed worse overall survival. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were utilized to investigate the potential mechanisms. The nine genes in ccRCC cells with erastin or RSL3 treatment were validated to find the crucial gene. The glutaminase 2 (GLS2) gene was upregulated during ferroptosis in ccRCC cells, and cells with GLS2 shRNA displayed lower survival, a lower glutathione level, and a high lipid peroxide level, which illustrated that GLS2 might be a ferroptotic suppressor in ccRCC.

The Crucial Role of AR-V7 in Enzalutamide-Resistance of Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) has the second highest incidence of malignancies occurring in men worldwide. The first-line therapy of PCa is androgen deprivation therapy (ADT). Nonetheless, most patients progress to castration-resistant prostate cancer (CRPC) after being treated by ADT. As a second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ) is the current mainstay of new endocrine therapies for CRPC in clinical use. However, almost all patients develop resistance during AR antagonist therapy due to various mechanisms. At present, ENZ resistance (ENZR) has become challenging in the clinical treatment of CRPC. AR splice variant 7 (AR-V7) refers to a ligand-independent and constitutively active variant of the AR and is considered a key driver of ENZR in CRPC. In this review, we summarize the mechanisms and biological behaviors of AR-V7 in ENZR of CRPC to contribute novel insights for CRPC therapy.