ncRNA-mediated overexpression of ubiquitin-specific proteinase 13 contributes to the progression of prostate cancer via modulating AR signaling, DNA damage repair and immune infiltration.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer, and the molecular mechanism driving mCRPC progression has not yet been fully elucidated. Immunotherapies such as chimeric antigen receptor, T-cell therapy and immune checkpoint blockade have exerted promising antitumor effects in hematological and solid tumor malignancies; however, no encouraging responses have been observed against mCRPC. The deubiquitinase USP13 functions as a tumor suppressor in many human cancers, as it sustains the protein stability of PTEN and TP53; however, its role in prostate cancer (PCa) and involvement in DNA damage and AR signaling remain unclear. In the current study, we explored the prognostic value of USP13 in PCa based on the TCGA database, and we analyzed the expression of USP13 in PCa tissues and adjacent normal tissues based on TCGA and our cohort. The results suggested that USP13 is overexpressed in PCa tumors and has the potential to be an independent biomarker for the overall survival of PCa patients. Additionally, enrichment analysis indicated that USP13 may participate in the AR pathway and PI3k/Wnt signaling, which are closely related to PCa progression. We also observed a significant correlation between the expression of USP13 and AR-related genes, DDR genes and mismatch repair genes based on the TCGA_PRAD dataset, which further supported the critical role of USP13 in AR activation and the DNA damage response of PCa. USP13 was also found to be enriched in protein neddylation, and expression of USP13 was significantly associated with infiltration of immune cells and expression of immunomodulators. Taken together, our study revealed a key role of USP13 in contributing to PCa progression by participating in multiple oncogenic signaling pathways, the DNA damage response and the immunosuppressive tumor microenvironment. Targeting USP13 may inhibit tumor growth and provide additional benefits in cooperation with DDR inhibitors and immunotherapy.

Cui X ，Yu H ，Yao J ，Li J ，Li Z ，Jiang Z ... -  《BMC CANCER》

AR expression-independent XRCC3 mediates DNA damage-induced p53/Bax signaling pathway activation against prostate cancer.

Androgen deprivation therapy (ADT) resistance is closely associated with altered AR status. Aberrant AR expression is critical for the induction of ADT resistance, necessitating the identification of an anti-PCa target independent of AR expression. Transcriptomic data and clinical information of PRAD were obtained from TCGA database. Genes with PCa-related and AR expression-independent were screened by bioinformatics, and characterized by PPI and GO functional enrichment analyses. Candidate genes were locked by co-expression correlation and disease-free survival (DFS) analyses. A prognostic gene set was established using LASSO Cox regression algorithm. Cox proportional risk regression was performed to identify a key prognostic gene. Expression of the target protein in PCa tissues was verified by The Human Protein Atlas database. In vitro validation of cellular function and molecular mechanism by knockdown and overexpression of the target gene. Two AR expression-independent genes (SLC43A1 and XRCC3) were available for the optimal prognostic model. This gene set effectively predicted PRAD patients' DFS at 1-, 3- and 5-year, where XRCC3 and tumor (T) stage were independent risk factors. XRCC3 was higher expressed in PRAD patients with T3-T4 stages and accompanied by poorer DFS. IHC staining also validated its higher expression in high-risk PCa tissues. In vitro experiments demonstrated that silencing XRCC3 significantly inhibited 22Rv1 and DU145 cell proliferation, migration and invasion, while promoted apoptosis. Further, silencing XRCC3 promoted DNA damage-induced p53/Bax signaling pathway activation, which was absent with overexpression. Silencing XRCC3 exerts anti-PCa effects by promoting DNA damage-induced p53/Bax signaling pathway activation in an AR expression-independent manner.

Xie H ，Dan M ，Cen Y ，Ning J ，Sun C ，Zhu G ，Feng S ，Wang H ，Pu J ... -  《-》

Identification of LAT/ZAP70 characterized immune subtypes of prostate cancer.

While immunotherapy has shown potent efficacy in clinical practices, patient selection to receive checkpoint blockade is still challenging in prostate cancer (PCa). LAT and ZAP70 functions in lymphocyte activation and plays a critical role in T cell receptor (TCR) signal transduction. However, PCa genomic and clinical data regarding the role of LAT and ZAP70 are limited. We aim to identify and characterize LAT/ZAP70 defined subtypes of PCa. We elaborated the TCGA PCa data and metastatic castration-resistant prostate cancer (mCRPC) RNA-seq data bioinformatic analysis and systematically elucidated the role of intra-tumoral expressed LAT and ZAP70 in the progression-free survival and immunotherapeutic-related signals. LAT/ZAP70-associated immune infiltration was evaluated using bioinformatic tools. Immunohistochemical staining of serial sections was used to confirm the expression and distribution of LAT, ZAP70 and androgen receptor (AR) in PCa tissues. Specifically, LAT and ZAP70 revealed increased expressions in PCa when compared to normal tissues and positively associated with intra-tumoral immune cells infiltration. LAT/ZAP70 defined immune-high early-stage PCa revealed higher TP53 mutation frequency and poor prognosis. Transcriptome analysis indicated immune-related signals and CTLA4 expression were highly enhanced in immune-high PCa parallel with higher protein level of MYC and lower AR expression. In mCRPC, LAT/ZAP70 defined immune-high patients also revealed upregulated immune related signals, higher CTLA4 expression and DNA repair deficiency. LAT/ZAP70 defined immune-high PCa linked to immune infiltration and predicts poor prognosis. Immune-high PCa may receive effective response from immune checkpoint inhibitor parallel with systemic treatment.

Yu J ，Gao W ，Gao S ，Wen S ，Zhao Y ，Shang Z ，Wang Y ，Niu Y ... -  《-》

Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function.

Gui B ，Gui F ，Takai T ，Feng C ，Bai X ，Fazli L ，Dong X ，Liu S ，Zhang X ，Zhang W ，Kibel AS ，Jia L ... -  《-》

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT.

Shen T ，Wang W ，Zhou W ，Coleman I ，Cai Q ，Dong B ，Ittmann MM ，Creighton CJ ，Bian Y ，Meng Y ，Rowley DR ，Nelson PS ，Moore DD ，Yang F ... -  《-》