Benign prostatic hyperplasia (BPH) is common in aging men, but the endothelial compartment in enlarged prostates remains poorly defined. In this hypothesis-generating pilot study, we generated a single-cell RNA-seq dataset from six surgically obtained BPH specimens (three Large BPH and three Small BPH) and analyzed 56,912 cells; public datasets GSE290213 and GSE242249 were used for external context. We observed a higher sample-level fraction of Activated endothelial cells and a lower fraction of Venous-like endothelial cells in Large BPH, but these descriptive summaries were not designed for formal group inference. RNA velocity, graph ordering, and focused Slingshot/tradeSeq analyses nominated a putative endothelial-state ordering; concordance between graph pseudotime and latent time was modest (Spearman rho = 0.252). Variance decomposition suggested that AP-1/NF-κB activity was largely linked to endothelial-state composition, whereas selected IFN/HLA-II-associated programs showed stronger group-linked genetic context. MAGMA and TWAS did not support Activated endothelial markers or Large-up endothelial genes as the main genetic signal; broader stromal-vascular and HLA-related patterns were more consistent with the genetic data. These findings nominate endothelial activation signatures and a two-axis exploratory model for future validation in larger clinically annotated cohorts with protein-level testing.

The goal of this study is to explore the genetic predictive associations between plasma proteomics and bladder cancer using the Mendelian randomization (MR) method, and to investigate whether plasma lipidomics characteristics mediate these associations. The genome-wide association study (GWAS) data for plasma proteins from deCODE Genetics included 4,907 aptamers for plasma proteins in 35,559 Icelandic individuals. Lipidomic GWAS data of 179 traits (GCST90277238–GCST90277416) were extracted from the GWAS Catalog, and bladder cancer GWAS summary statistics were sourced from FinnGen R8 (2,380 cases and 259,583 controls). Two-sample MR evaluated the causal links between genetically predicted plasma proteins and bladder cancer risk; mediation MR further examined mediating roles of lipidomic. Primary causal analyses adopted the MR Wald ratio and inverse variance-weighted approaches. Heterogeneity was tested by the Cochrane Q test, horizontal pleiotropy by MR-Egger intercept test, and leave-one-out analysis was used for sensitivity assessment. Our findings suggest that genetically predicted levels of 29 proteins may be associated with the risk of bladder cancer. Among these, 17 proteins showed inverse associations with bladder cancer risk, while 12 proteins showed positive associations. A negative mediation proportion indicates that the estimated direction of the indirect effect is opposite to that of the total effect. For example, the mediation proportion of −56

LINC00525, a long noncoding RNA (lncRNA), has been implicated in the regulation of cancer progression across various types. However, its role in bladder cancer (BLCA) remains unconfirmed. In this study, we observed upregulation of LINC00525 expression in both bladder cancer tissues and cell lines compared to normal controls. Among the 12 pairs of collected tissue samples, LINC00525 exhibited higher expression levels in muscle-invasive bladder cancer (MIBC) tissues than in non-muscle-invasive bladder cancer (NMIBC) tissues, indicating a positive correlation between LINC00525 levels and bladder cancer progression. In vitro experiments demonstrated that knockdown of LINC00525 significantly inhibited proliferation, migration, and invasion of bladder cancer cell lines; conversely, overexpression of LINC00525 had the opposite effect. Bioinformatic analysis revealed an association between LINC00525 and YAP, which was further confirmed by western blotting and PCR analysis using patient tissues. Mechanistically, we found that LINC00525 reduced phosphorylation of YAP at serine 127 (S127), promoting its nuclear import to exert transcriptional regulatory effects on target genes. Additionally, LINC00525 inhibited YAP ubiquitination by acting on YAP lysine 321 (K321), thereby increasing its stability to prevent degradation. Through in vivo and in vitro experiments, we demonstrated the YAP-mediated promoting effect of LINC00525 on bladder cancer cells and tumor growth. Our study reveals the involvement of the LINC00525/YAP axis in regulating bladder cancer development, suggesting a potential therapeutic strategy for malignant tumors characterized by high levels of LINC00525 expression.

BACKGROUND:Bladder cancer (BCa) is one of the most common types of cancers prevalent in the global populace, and it is predominantly detected among men. The role of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in promoting invasion and metastasis in cancers is well known. Despite this, the precise regulatory mechanism by which CEACAM6 contributes to BCa progression remain poorly understood, which is precisely the focus of the present study. METHODS:Our research generated BCa cell lines with CEACAM6 overexpression/knockdown to evaluate the functional significance of CEACAM6. We assessed how the modulation of CEACAM6 influences cell proliferation both in vitro and in vivo on BCa progression. In addition, the effect of CEACAM6 on glycolytic activity was also explored. The co-localization, co-immunoprecipitation, ubiquitination studies, and rescue experiments were performed to understand the molecular interaction between CEACAM6 and alpha-Enolase 1 (ENO1). RESULTS:Our data show that high CEACAM6 expression promotes proliferation, invasion, migration, and clonogenicity of BCa cells. Additionally, CEACAM6 binding to ENO1 and maintain its stability, leading to increased glycolytic activity and invasiveness and proliferative of BCa cells. CONCLUSION:Our study demonstrated that CEACAM6 regulates glycolysis via the ENO1-AKT/mTOR axis. These results offer new evidence about previously unexplored molecular mechanisms driving BCa progression.

The emergence of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT) is associated with increased malignancy and limited treatment options. This study aims to investigate potential connections between immune cell infiltration and inflammatory cytokines with the YAP1/AR/PSA axis by exploring their interactions with autophagy. Our research reveals heightened levels of Yes-associated protein 1 (YAP1) expression in CRPC tissues compared with tissues from androgen-dependent prostate cancer (ADPC) and benign prostate hyperplasia (BPH). Additionally, a correlation was observed between YAP1 and PSA expressions in CRPC tissues, suggesting that YAP1 may exert a regulatory influence on PSA expression within CRPC. Enhanced YAP1 expression in C4-2 cells resulted in the upregulation of androgen receptor (AR) nuclear translocation and intracellular prostate-specific antigen (PSA) levels. Conversely, the suppression of YAP1 led to a decrease in PSA expression, suggesting that YAP1 may positively regulate the PSA in castration-resistant prostate cancer (CRPC) by facilitating AR nuclear import. The modulation of the autophagy activity exerts a significant impact on the expression levels of YAP1, the AR, and the PSA. Moreover, recent advancements in immunity and inflammation studies present promising avenues for potential therapies targeting prostate cancer (PC).

In American men, the incidence of prostate cancer (PC) is the highest among all types of cancer, making it the second leading cause of mortality associated with cancer. For advanced or metastatic PC, antiandrogen therapies are standard treatment options. The administration of these treatments unfortunately carries the potential risk of inducing neuroendocrine prostate cancer (NEPC). Neuroendocrine differentiation (NED) serves as a crucial indicator of prostate cancer development, encompassing various factors such as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), Yes-associated protein 1 (YAP1), AMP-activated protein kinase (AMPK), miRNA. The processes of autophagy and ferroptosis (an iron-dependent form of programmed cell death) play pivotal roles in the regulation of various types of cancers. Clinical trials and preclinical investigations have been conducted on many signaling pathways during the development of NEPC, with the deepening of research, autophagy and ferroptosis appear to be the potential target for regulating NEPC. Due to the dual nature of autophagy and ferroptosis in cancer, gaining a deeper understanding of the developmental programs associated with achieving autophagy and ferroptosis may enhance risk stratification and treatment efficacy for patients with NEPC.

Ubiquitination, a prevalent and highly dynamic reversible post-translational modification, is tightly regulated by the deubiquitinating enzymes (DUBs) superfamily. Among them, OTU Domain-Containing Ubiquitin Aldehyde-Binding Protein 1 (OTUB1) stands out as a critical member of the OTU deubiquitinating family, playing a pivotal role as a tumor regulator across various cancers. However, its specific involvement in BLCA (BLCA) and its clinical significance have remained ambiguous. This study aimed to elucidate the biofunctions of OTUB1 in BLCA and its implications for clinical prognosis. Our investigation revealed heightened OTUB1 expression in BLCA, correlating with unfavorable clinical outcomes. Through in vivo and in vitro experiments, we demonstrated that increased OTUB1 levels promote BLCA tumorigenesis and progression, along with conferring resistance to cisplatin treatment. Notably, we established a comprehensive network involving OTUB1, β-catenin, necroptosis, and BLCA, delineating their regulatory interplay. Mechanistically, we uncovered that OTUB1 exerts its influence by deubiquitinating and stabilizing β-catenin, leading to its nuclear translocation. Subsequently, nuclear β-catenin enhances the transcriptional activity of c-myc and cyclin D1 while suppressing the expression of RIPK3 and MLKL, thereby fostering BLCA progression and cisplatin resistance. Importantly, our clinical data suggest that the OTUB1/β-catenin/RIPK3/MLKL axis holds promise as a potential biomarker for BLCA.

8054 Background: Neoadjuvant PD-1 inhibitor plus chemotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. hypofractioned radiotherapy (HFRT) served as an immunomodulator and enhanced the effect of preoperative immunotherapy. In this phase Ib study, we evaluated the safety and feasibility of neoadjuvant HFRT with pembrolizumab plus chemotherapy in patients with potentially resectable stage III NSCLC. Methods: Patients with potentially resectable stage III NSCLC with EGFR/ALK wild-type were recruited to receive HFRT to the primary tumor followed by two cycles of pembrolizumab (100 mg/body) plus platinum-based doublet chemotherapy (Q3W). HFRT was delivered using 3 daily fractions, with a dose of 24 Gy for peripheral lesions and 12 Gy for central lesions. Central lesion is defined as a 2 cm area around the pulmonary artery and main bronchus. The decision for surgery was made through multidisciplinary team (MDT) discussion within a 4–6-week period after the completion of neoadjuvant treatment. Patients underwent surgery followed by adjuvant pembrolizumab for 2 years. Primary endpoint was safety. Secondary endpoints were efficacy, such as pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: Between April 2021 and November 2023, 17 patients were enrolled with a median age of 66 years (range 54-74) and 15 (88.2%) having squamous cell lung cancer. 12 (70.6%) patients had stage IIIB disease, and 10 (58.8%) had central primary lesion. PD-L1 was ≥1% in 9 patients (52.9%). All patients received HFRT and at least one cycle of immunochemotherapy. No grade 3 or high adverse events were observed during neoadjuvant therapy. Only one patient had grade 1 nephrotoxicity, and another patient had grade 2 pneumonitis. A partial response was achieved in 16 out of 17 patients (94.1%), while one patient had stable disease after neoadjuvant therapy. Following MDT discussion, 11 patients (64.7%) met the surgical standards, while the remaining 6 patients were transitioned to definitive chemoradiotherapy. Among the 11 patients who underwent surgery, 8 (72.7%) achieved R0 resection, and 6 patients (54.5%) attained pCR. Only one patient died from intraoperative bleeding, and the remaining patients were followed up. The median PFS was 21.7 months, median OS were not reached, and the 2-year OS rate was 85.6%. The study was terminated early due to slow recruitment. Conclusions: Neoadjuvant HFRT with immunotherapy for potentially resectable stage III NSCLC is a tolerable treatment with an improved surgical conversion rate and pCR rate. Clinical trial information: ChiCTR2100045361.

Prostate cancer is a major disease that threatens men’s health. Its rapid progression, easy metastasis, and late castration resistance have brought obstacles to treatment. It is necessary to find new effective anticancer methods. Ferroptosis is a novel iron-dependent programmed cell death that plays a role in various cancers. Understanding how ferroptosis is regulated in prostate cancer will help us to use it as a new way to kill cancer cells. In this review, we summarize the regulation and role of ferroptosis in prostate cancer and the relationship with AR from the perspective of metabolism and molecular pathways. We also discuss the feasibility of ferroptosis in prostate cancer treatment and describe current limitations and prospects, providing a reference for future research and clinical application of ferroptosis.

Objectives:To analyze the correlations between the expression and effect of DNA damage repair genes and the immune status and clinical outcomes of urothelial bladder cancer (BLCA) patients. In addition, we evaluate the efficacy and value of utilizing the DNA damage repair genes signature as a prognosis model for BLCA. Methods:Two subtype groups (C1 and C2) were produced based on the varied expression of DNA damage repair genes. Significantly differentiated genes and predicted enriched gene pathways were obtained between the two subtypes. Seven key genes were obtained from the DNA damage repair-related genes and a 7-gene signature prognosis model was established based on the key genes. The efficacy and accuracy of this model in prognosis prediction was evaluated and verified in two independent databases. Also, the difference in biological functions, drug sensitivity, immune infiltration and affinity between the high-risk group and low-risk group was analyzed. Results:The DNA damage repair gene signature could significantly differentiate the BLCA into two molecular subgroups with varied genetic expression and enriched gene pathways. Seven key genes were screened out from the 232 candidate genes for prognosis prediction and a 7-gene signature prognosis model was established based on them. Two independent patient cohorts (TCGA cohort and GEO cohort) were utilized to validate the efficacy of the prognosis model, which demonstrated an effective capability to differentiate and predict the overall survival of BLCA patients. Also, the high-risk group and low-risk group derived from the 7-gene model exhibited significantly differences in drug sensitivity, immune infiltration status and biological pathways enrichment. Conclusions:Our established 7-gene signature model based on the DNA damage repair genes could serve as a novel prognosis predictive tool for BLCA. The differentiation of BLCA patients based on the 7-gene signature model may be of great value for the appropriate selection of specific chemotherapy agents and immune-checkpoint blockade therapy administration.

The involvement of necroptosis in the immunosuppressive tumor microenvironment has been established and has been shown to contribute to the growth of pancreatic ductal adenocarcinoma, indicating its role in promoting tumor development. However, the relationship between necroptosis and bladder urothelial carcinoma (BUC) has yet to be fully understood. To shed light on this issue, our study aimed to uncover the impact of necroptosis on immune cell infiltration and immunotherapy response in BUC patients. We conducted an analysis of 67 necroptosis genes to assess their expression and genomic changes across pan-cancer and identified 12 necroptosis genes that are prognostically relevant and associated with immune subtypes and tumor stemness in BUC. Using a public database of 1841 BUC samples, we then performed Unsupervised Cluster Analysis and discovered two distinct necroptotic phenotypes in BUC. These phenotypes showed significant differences in molecular subtypes, immune infiltration patterns, and gene mutation profiles. We confirmed this discovery in BUC through qPCR and WB experiments. To evaluate the impact of necroptosis on prognosis, chemotherapy sensitivity, and immunotherapy response (such as anti-PD-L1), we developed a principal component analysis model called NecroScore. Finally, we validated the effects of RIPK3 and MLKL through a nude mouse transplantation model for BUC. Our study has uncovered that necroptosis plays a role in shaping the tumor immune microenvironment in BUC. The high necroptosis phenotype (Cluster B) was characterized by a higher abundance of tumor immunosuppressive cells and more key biological processes driving tumor progression, while the low necroptosis group (Cluster A) had higher FGFR3 mutations. We found that the infiltration levels of immune cells, including CD8+ T cells, were significantly different between FGFR3 mutated and wild-type (WT) samples. Our results confirmed the reliability of NecroScore as a comprehensive assessment tool for evaluating the immunotherapeutic effect and prognosis of BUC patients, with high NecroScore values favoring basal-like differentiation and lower FGFR3 alterations. We also observed that high expression of MLKL had a significant inhibitory effect on tumor growth and increased neutrophil infiltration in vivo. In our study, we uncovered the regulation pattern of necroptosis in the tumor immune microenvironment of BUC. Additionally, we developed a scoring tool called NecroScore that can be utilized to predict the most suitable chemotherapy and immunotherapy strategy for bladder urothelial carcinoma patients. This tool can effectively guide the chemotherapy and immunotherapy regimens for patients with advanced BUC.

The development of castration-resistant prostate cancer (CRPC) is driven by intricate genetic and epigenetic mechanisms. Traf2- and Nck-interacting kinase (TNIK) has been reported as a serine/threonine kinase associated with tumor cell proliferation or unfavorable cancer behavior. The microarray approach revealed a substantial upregulation of TNIK expression levels, enabling us to investigate the functional behaviors of the TNIK gene in CRPC. Specifically, we discovered that AR suppresses TNIK gene transcription in LNCaP and C4-2 cells by forming a complex with H3K27me3. Following the reduction of AR levels induced by androgen deprivation therapy (ADT), TNIK is recruited to activate EGFR signaling through phosphorylation in C4-2 cells, thereby promoting CRPC progression. Our findings unveil a regulatory role of AR as a repressor for TNIK while also highlighting how TNIK activates the EGFR pathway via phosphorylation to drive CRPC progression. Consequently, targeting TNIK may represent an appealing therapeutic strategy for CRPC.

Objective The aim of this study was to construct a collagen-related prognostic model for thyroid cancer and to investigate prognostic value of collagen family genes for thyroid cancer. Methods A LASSO Cox regression model for thyroid cancer was developed based on the expression profiles of collagen-related genes. Kaplan-Meier survival analysis was performed for high and low risk groups. The ROC method was used to assess its predictive performance. Predictive independence was verified by multivariate Cox regression analysis. The relationship between this feature and immune cell infiltration was analyzed by tumor microenvironment. COL18A1 was validated by immunohistochemistry and RT-PCR in thyroid cancer tissues. The effect of COL18A1 on cell proliferation, migration and invasion ability of tumor cells were further valuated by CCK-8 assay and transwell assay. The effect of COL18A1 on the immune escape ability of tumor cells was further valuated by cytotoxicity assays. Results A model including 4 collagen family genes was developed to predict thyroid cancer prognosis. Patients with high-risk score had a poorer prognosis than those with low-risk scores for 1-, 2-, 3-, and 5- year survival. The model independently predicted prognosis after adjusting for other prognostic factors. A nomogram combining risk score and age was constructed with high sensitivity and specificity. This feature was significantly associated with immune cell infiltration. COL18A1 was aberrantly over-expressed in thyroid cancer compared with control tissues and significantly increased proliferative capacity, migration capacity, invasion capacity, and immune escape ability of tumor cells. Conclusion Our findings establish a signature associated with collagen family genes that can be a promising tool to predict the prognosis of thyroid cancer. High COL18A1 expression significantly correlates with the poor prognosis of patients and enhances the immune escape ability of tumor cells.

Objective: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer (PC) that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. In our investigation, there appeared to be a strong correlation between neuroendocrine differentiation prostate cancer (NEDPC) and NEPC. The objectives of this study included exploring whether NEDPC is an intermediate stage in the progression of high-risk prostate cancer (HRPC) to NEPC and identifying risk factors and new targets associated with survival in the treatment of NEPC. Methods: The selected prostate cancer patients were progressed to high-risk and characterized by neuroendocrine. We collected the clinical data and characteristics of patients with three types of cancer: the incidence of metastasis, site and time of metastasis, recurrence rate, related treatment methods, etc. The similarity and differences of the three groups were compared through experiment and database. Results: By analyzing the clinical data and immunohistochemical results, we found that there seems to be a clinical feature of neuroendocrine differentiation (NED) status in between when patients progress from PC to NEPC. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC. The metastasis-free survival curve and the immunohistochemical results are informing us that NEDPC can be a pre-state for diagnosing NEPC. Conclusion: NEPC is a late PC symptom that is frequently disregarded and has a bad prognosis. Finding novel treatment targets would therefore be beneficial by taking into account NEDPC as the stage of PC progression prior to NEPC.

OTU domain-containing ubiquitin aldehyde-binding proteins 1 (OTUB1) is the most important element of the deubiquitinase OTU superfamily, which has been identified as an essential regulator of diverse physiological processes, such as DNA damage repair and cytokines secretion. Recently, we found that the pro-carcinogenesis role of OTUB1 and the relationship between OTUB1 and immune response have gradually become the research hot-spot. OTUB1 regulates NK/CD8 T cell activation, autoimmune diseases, PD-L1 mediated immune evasion, viral or bacterial infection related immune response and the occurrence and progression of various cancers via deubiquitinating and stabilizing related proteins. This review provides a comprehensive description about the role and regulatory axis of OTUB1. We can explore the balance between immune response and defense via regulating the level of OTUB1, and targeting OTUB1 might restrain the progression of cancers. This review highlights the experimental evidence that OTUB1 is a feasible and potential therapeutic target against various cancers progression and immune diseases or disorder.

Liver transplantation is the only treatment available for pediatrics with end-stage liver disease. However, neurological damage is prone to occur after liver transplantation, especially in children. Accumulating evidence has shown that sevoflurane is closely linked to brain injury induced by liver transplantation. However, the study on the role of sevoflurane in brain injury induced by liver transplantation is rare and needs to be further investigated. The study is aiming to investigate the effects of sevoflurane on brain injury induced by liver transplantation and its underlying mechanisms. The brain injury rat model was built through 70% hepatic ischemia-reperfusion (HIR) of young rats. We detected the ferroptosis and brain injury after HIR by histological, transmission electron microscope analyses, western blot, and Enzyme-linked immunosorbent assays. And we detected the level of ferroptosis in brain by using sevoflurane during HIR compared with HIR without using sevoflurane. At the same time, we use iron inhibitor deferoxamine (DFO) to verify that the brain injury was caused by ferrotosis of brain. The results indicated that the pathological injury, ferroptosis indicators, and brain injury indicators were aggravated in the sevoflurane group compared with the HIR group, the decrease in the degree of brain injury and ferroptosis was observed in the group using DFO. Collectively, the results suggest that ferroptosis may mediate sevoflurane-aggravated young rats' brain injury induced by liver transplantation. Our findings provide a potential therapeutic target for brain injury after pediatric liver transplantation.

Ubiquitination is a critical biological process in post-translational modification of proteins and involves multiple signaling pathways in protein metabolism, apoptosis, DNA damage, cell-cycle progression, and cancer development. Deubiquitinase, a specific enzyme that regulates the ubiquitination process, is also thought to be closely associated with the development and progression of various cancers. In this article, we systematically review the emerging role of the deubiquitinase ubiquitin-specific peptidase 11 (USP11) in many cancer-related pathways. The results show that USP11 promotes or inhibits the progression and chemoresistance of different cancers, including colorectal, breast, ovarian, and hepatocellular carcinomas, via deubiquitinating several critical proteins of cancer-related pathways. We initially summarize the role of USP11 in different cancers and further discuss the possibility of USP11 as a therapeutic strategy.

A common stage of advanced prostate cancer is castration-resistant prostate cancer (CRPC), greater understanding of which is required in order to address and solve the clinically difficult challenge. Cathepsin K (CTSK) is a cysteine protease that usually has a strong activity of degrading extracellular matrix and is related to osteoclast-mediated bone destruction. However, the mechanism of CTSK-regulation in CRPC is still unclear to us. The current study aimed to analyze the expression of differentially expressed genes (DEGs) in patient samples (from localized PC and CRPC). Interestingly, we found that CTSK to be significantly up-regulated in CRPC. Through further signal pathway enrichment analysis, we found that the IL-17 signaling pathway to be highly correlated with CTSK. The oncogenic functions of CTSK and IL-17 in CRPC were proven by a series of in vivo and in vitro experiments. Possible downstream molecules of CTSK were investigated, which could serve as control elements to regulate the expression of EMT, thereby facilitating the metastasis and excessive proliferation of PC cells. Expression of CTSK was related to high concentration of M2 tumor-associated macrophages (TAMs) M2 in CRPC. A CTSK-mediated feedback circuit between TAMs and CRPC tissues was indicated in the process of transfer, proving the possibility of CTSK could be use as an available therapeutic target for CRPC.

Background: Prostate cancer (PCa) is currently the most common cancer among males worldwide. It has been reported that OTUB1 plays a critical role in a variety of tumors and is strongly related to tumor proliferation, migration, and clinical prognosis. The aim of this research is to investigate the regulatory effect of OTUB1 on PCa proliferation and the underlying mechanism.Methods: Using the TCGA database, we identified that OTUB1 was up-regulated in PCa, and observed severe functional changes in PC3 and C4-2 cells through overexpression or knock down OTUB1. Heterotopic tumors were implanted subcutaneously in nude mice and IHC staining was performed on tumor tissues. The relationship between OTUB1 and cyclin E1 was identified via Western blotting and immunoprecipitations assays.Results: We found that the expression of OTUB1 in PCa was significantly higher than that in Benign Prostatic Hyperplasia (BPH). Overexpression OTUB1 obviously promoted the proliferation and migration of PC3 and C4-2 cells via mediating the deubiquitinated Cyclin E1, while OTUB1 knockout has the opposite effect. The nude mice experiment further explained the above conclusions. We finally determined that OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabling Cyclin E1.Conclusions: Our findings reveal the critical role of OTUB1 in PCa, and OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabilizing Cyclin E1. Blocking OTUB1/Cyclin E1 axis or applying RO-3306 could significantly repress the occurrence and development of PCa. OTUB1/Cyclin E1 axis might provide a new and potential therapeutic target for PCa.

Prostate cancer is a common malignant tumor, which can spread to multiple organs in the body. Metastatic disease is the dominant reason of death for patients with prostate cancer. Prostate cancer usually transfers to bone. Bone metastases are related to pathologic fracture, pain, and reduced survival. There are many known targets for prostate cancer treatment, including androgen receptor (AR) axis, but drug resistance and metastasis eventually develop in advanced disease, suggesting the necessity to better understand the resistance mechanisms and consider multi-target medical treatment. Because of the limitations of approved treatments, further research into other potential targets is necessary. Metastasis is an important marker of cancer development, involving numerous factors, such as AKT, EMT, ECM, tumor angiogenesis, the development of inflammatory tumor microenvironment, and defect in programmed cell death. In tumor metastasis, programmed cell death (autophagy, apoptosis, and necroptosis) plays a key role. Malignant cancer cells have to overcome the different forms of cell death to transfer. The article sums up the recent studies on the mechanism of bone metastasis involving key regulatory factors such as macrophages and AKT and further discusses as to how regulating autophagy is crucial in relieving prostate cancer bone metastasis.