To investigate the association of immunosenescence with aged-related morbidity in the elderly, a clinical study was conducted to analyze and compare the alterations in peripheral blood (PB) T-cell subsets among young healthy (YH) controls, elderly healthy (EH) controls, and age-matched elderly patients with metabolic diseases (E-MDs), with cardiovascular diseases (E-CVDs) or with both (E-MDs/E-CVDs). The frequencies of CD3T, CD8T and invariant natural killer T (iNKT) cells were decreased in the EH, E-MD and E-CVD cohorts, indicating a decline in defense function. Although CD4T and regulatory T (Treg) cell frequencies tended to increase with aging, they were lower in patients with E-MDs and E-CVDs. Subset analyses of T-cells consistently showed the accumulation of senescent T-cell in aging and in patients with E-MDs and E-CVDs, compared with YH volunteers. These accumulated senescent T-cells were undergoing apoptosis upon stimulation due to the replicative senescence stage of T-cells. In addition, serum levels of cytokines, including interferon (IF)-γ, transforming growth factor (TGF)-β and growth differentiation factor (GDF)-15, consistently reflected alterations in T-cell subsets. This study demonstrated that T-cell subset changes with paralleled alterations in cytokines were associated with aging and age-related pathogenesis. These altered T-cell subsets and/or cytokines can potentially serve as biomarkers for the prevention, diagnosis and treatment of age-related morbidities.
Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.
Prostate cancer (PCa) is one of the most prevalent cancers in men, yet its pathogenic pathways remain poorly understood. Transcriptomics and high-throughput sequencing can help uncover cancer diagnostic targets and understand biological circuits. Using prostate adenocarcinoma (PRAD) datasets of various web-based applications (GEPIA, UALCAN, cBioPortal, SR Plot, hTFtarget, Genome Browser, and MetaCore), we found that upregulated dysbindin domain-containing 1 (DBNDD1) expression in primary prostate tumors was strongly correlated with pathways involving the cell cycle, mitotic in KEGG, WIKI, and REACTOME database, and transcription factor-binding sites with the DBNDD1 gene in prostate samples. DBNDD1 gene expression was influenced by sample type, cancer stage, and promoter methylation levels of different cancers, such as PRAD, liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD). Regulation of glycogen synthase kinase (GSK)-3β in bipolar disorder and ATP/ITP/GTP/XTP/TTP/CTP/UTP metabolic pathways was closely correlated with the DBNDD1 gene and its co-expressed genes in PCa. DBNDD1 gene expression was positively associated with immune infiltration of B cells, Myeloid-derived suppressor cell (MDSC), M2 macrophages, andneutrophil , whereas negatively correlated with CD8+ T cells, T follicular helper cells, M1 macrophages, and NK cells in PCa. These findings suggest that DBNDD1 may serve as a viable prognostic marker not only for early-stage PCa but also for immunotherapies.
Androgen deprivation therapy (ADT)-induced neuroendocrine differentiation (NED) is a well-known lethal subtype of prostate cancer (PCa) with a median survival rate of less than one year. Despite the increasing research attention on this variant of PCa, the underlying mechanism orchestrating therapy-related neuroendocrine prostate cancer (NEPC) remains elusive. We found that ADT-induced hypoxia-associated ZBTB46/FOXA2/HIF1A signaling enhances the multiple C2 domain transmembrane protein 1 (MCTP1), which promotes NED and epithelial-to-mesenchymal transition (EMT) of PCa. Mechanistically, ZBTB46 physically interacts with the HIF1A/FOXA2 complex, in which ZBTB46 may be a co-activator of the hypoxia-related FOXA2 transcription factor. Interestingly, this ZBTB46/FOXA2/HIF1A complex accumulates after hypoxia and functions as a transcriptional activator of MCTP1. Hypoxia-upregulated MCTP1 subsequently leads to NED and the increase in EMT, whereas the opposite is true for the knockdown of MCTP1 in PCa cells. Consistent with previous results, MCTP1 is highly expressed in high-grade castration-resistance prostate cancer (CRPC) and small-cell PCa (SCPC) tissues and is associated with NE markers and ZBTB46/FOXA2/HIF1A abundance. In this study, we explored the direct interaction of ZBTB46 protein with hypoxia-related FOXA2/HIF1A complex in PCa cells under hypoxic conditions, which promote MCTP1-driven EMT and NED. Our finding suggests that MCTP1 could be used as a biomarker for diagnosing NEPC and as a therapeutic target in clinical applications. Citation Format: Vu Thuy Dung Phan, Yu-Ching Wen, Wei-Yu Chen, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Van Thi Ngoc Tram, Zi-Qing Chen, Wan-Hsin Wang, Yen-Nien Liu. ZBTB46/FOXA2/HIF1A transcription activator complex promotes MCTP1-regulated neuroendocrine differentiation and epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3736.
Neuroendocrine differentiation (NED) frequently occurs in androgen-deprivation therapy (ADT)-resistant prostate cancer (PCa) and is typically associated with metabolic pathway alterations, acquisition of lineage plasticity, and malignancy. There is no conventional therapeutic approach for PCa patients with NED pathologic features because the molecular targets are unknown. Here, we evaluated the regulatory mechanism of NED-associated metabolic reprogramming induced by ADT. We detected that the loss of the androgen-responsive transcription factor, zinc finger, and BTB domain containing 10 (ZBTB10), can activate pyruvate kinase L/R (PKLR) to enhance a NED response that is associated with glucose uptake by PCa cells. PKLR exhibits a tumor-promoting effect in PCa after ADT, but ZBTB10 can compensate for the glucose metabolism and NED capacity of PKLR through the direct transcriptional downregulation of PKLR. Targeting PKLR by drug repurposing with FDA-approved compounds can reduce the aggressiveness and NED of ADT-resistant PCa. We demonstrated that PKLR acts as a modulator to activate NED in PCa enhancement by loss of ZBTB10, thereby enabling PCa cells to mount a glycolysis response essential for therapeutic resistance. Our findings highlight the broad relation between NED and metabolic dysfunction to provide gene expression-based biomarkers for NEPC treatment.
Ageing of the immune system (immunosenescence (ISC)), is a complex subject characterized by a decrease in cell-mediated immunity, particularly with T-cell function. We conducted a clinical study to analyze peripheral blood (PB) for alterations in T-cell subsets among young healthy (YH) controls, elderly healthy (EH) controls, age-matched subjects with metabolic diseases (MDs; E-MDs), and cardiovascular diseases (CVDs; E-CVDs). The frequencies of expressions of CD3T, CD8T, and invariant natural killer T (NKTs; iNKT) cells were reduced in the EH, E-MD, and E-CVD cohorts; in contrast, CD4T and regulatory T (Treg) cell frequencies tended to increase with ageing, whereas they were lower in subjects with aged-related MDs and CVDs. Moreover, subsets including naïve, effector memory T (TEM) cells, effector memory T cells re-expressing CD45RA (TEMRA), as well as the CD28−CD57+phenotype in the CD4T and CD8T subpopulations consistently showed accumulation of senescent T-cell subsets in ageing, and in patients with E-MDs and E-CVDs compared to YH volunteers. Notably, serum cytokines, including Interferon (IFN)-γ, Transforming growth factor (TGF)-β, and Growth differentiation factor (GDF)-15 levels were consistently reflection of the alterations in T-cell subsets for within-group comparisons. Ageing-, E-MD-, and E-CVD-associated changes in PB T-cell subsets were paralleled by alterations in expressions of cytokines involved in lymphopoiesis, which might play important roles in ageing, and aged-related MD- and CVD-mediated dysregulation of immune functions. Furthermore, identifying these altered T-cell subsets can potentially serve as diagnostic markers for preventing ageing problems and treating aged-related MDs and CVDs.
Background Prostate cancer (PCa) patients with bone metastases frequently exhibit abnormal calcium homeostasis. However, the molecular mechanisms underlying bone metastasis mediated by activated calcium transport signaling remain unclear. Our results showed that androgen deprivation therapy (ADT) of PCa upregulates a calcium sensor transmembrane protein, the multiple C2 domains transmembrane protein 1 (MCTP1), which is upregulated by hypoxia-induced ZBTB46/FOXA2/HIF1A signaling and is associated with SNAI1-driven neuroendocrine (NE) differentiation (NED) and epithelial-to-mesenchymal transition (EMT) in PCa. Methods Hypoxia induced interactions between ZBTB46, HIF1A, and FOXA2 were confirmed by immunoprecipitation (IP)-Western Blot (WB). Correlation between MCTP1 and ZBTB46/FOXA2/HIF1A complexes was analyzed by immunohistochemical (IHC) staining in consecutive tissue sections of PCa tissue microarray (TMA) comprising primary PCa and small cell PCa (SCPC) samples. The regulatory network between MCTP1 and the hypoxia-induced ZBTB46/FOXA2/HIF1A axis was investigated by chromatin IP (ChIP)-Seq analysis, ChIP assay, and promoter reporter assays. The effect of MCTP1 on SNAI1 expression driving NED and EMT in PCa was identified in PCa cell lines using mimic hypoxia, ADT, or long-term androgen receptor (AR) antagonist culture systems. Activation of the MCTP1-mediated calcium-related pathway induces SNAI1-driven NED and aggressive progression of PCa under hypoxic conditions was examined by Fluo-8 AM staining combined with flow cytometry, migration, invasion, and xenograft model validation. Results MCTP1 is highly expressed in advanced PCa tissues and is associated with ZBTB46/FOXA2/HIF1A abundance. Upregulation of MCTP1 enhances SNAI1-mediated cell migration and EMT responses and is associated with hypoxia-driven NED in PCa after ADT. Mechanistically, hypoxia enhances the MCTP1-mediated calcium/AKT pathway to stabilize SNAI1 in PCa to promote EMT and NED by increasing the SNAI1-driven expression of EMT and NE markers. MCTP1 knockdown abrogated hypoxia-enhanced EMT and NED by reducing calcium/AKT pathway-driven SNAI1 expression. Conclusions Our study shows the molecular mechanism by which hypoxia-associated ZBTB46/FOXA2/HIF1A transcription factor interaction upregulates the calcium sensor transmembrane protein MCTP1 in ADT-resistant PCa, and explores how MCTP1 promotes NED and EMT in PCa by upregulating SNAI1-driven EMT and NE markers.
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