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Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.
Assuntos
Histonas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Histonas/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Lisina/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Metiltransferases/metabolismo , Histona Desmetilases/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismoRESUMO
The androgen receptor (AR) plays a pivotal role in driving prostate cancer (PCa) development. However, when stimulated by high levels of androgens, AR can also function as a tumor suppressor in PCa cells. While the high-dose testosterone (high-T) treatment is currently being tested in clinical trials of castration-resistant prostate cancer (CRPC), there is still a pressing need to fully understand the underlying mechanism and thus develop treatment strategies to exploit this tumor-suppressive activity of AR. In this study, we demonstrate that retinoblastoma (Rb) family proteins play a central role in maintaining the global chromatin binding and transcriptional repression program of AR and that Rb inactivation desensitizes CRPC to the high-dose testosterone treatment in vitro and in vivo. Using a series of patient-derived xenograft (PDX) CRPC models, we further show that the efficacy of high-T treatment can be fully exploited by a CDK4/6 inhibitor, which strengthens the chromatin binding of the Rb-E2F repressor complex by blocking the hyperphosphorylation of Rb proteins. Overall, our study provides strong mechanistic and preclinical evidence on further developing clinical trials to combine high-T with CDK4/6 inhibitors in treating CRPC.
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Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Linhagem Celular Tumoral , Cromatina , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/uso terapêutico , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/uso terapêutico , Genes Supressores de Tumor , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteína do Retinoblastoma/genética , Testosterona/uso terapêuticoRESUMO
Photoinduced metal-organic framework (MOF) enabled heterogeneous thiol catalysis has been achieved for the first time. MOF Zr-TPDCS-1, consisting of Zr6 -clusters and TPDCS linkers (TPDCS=3,3'',5,5''-tetramercapto[1,1':4',1''-terphenyl]-4,4''-dicarboxylate), effectively catalyzed the borylation, silylation, phosphorylation, and thiolation of organic molecules. Upon irradiation, the fast electron transfer from TPDCS to Zr6 -cluster is believed to facilitate the formation of the thiyl radical, a hydrogen atom transfer catalyst, which competently abstracts the hydrogen from borane, silane, phosphine, or thiol for generating the corresponding element radical to engender the chemical transformations. The elaborate control experiments evidenced the generation of thiyl radicals in MOF and illustrated a radical reaction pathway. The gram-scale reaction worked well, and the product was conveniently separated via centrifugation and vacuum with a turnover number (TON) of ≈3880, highlighting the practical application potential of heterogeneous thiyl-radical catalysis.
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Estruturas Metalorgânicas , Compostos de Sulfidrila , Compostos de Sulfidrila/química , Catálise , Hidrogênio/químicaRESUMO
We employ facile aromatic nucleophilic substitution between the mercapto (-SH) and arylfluoro (Ar-F) groups to achieve extensive and robust cross-linking of a coordination host by porphyrin guests that also serve the purpose of versatile postsynthetic functionalization. For this, a tritopic linker with three trident-like thiol-flanked carboxyl units are reacted with ZrOCl2·8H2O to afford a two-dimensional (3,6-connected) net. The wide aperture of the porous framework solid, together with its stability in both air and boiling water, facilitates the entry of bulky metalloporphyrin guests and the subsequent property studies. On the porphyrin side, four pentafluorophenyl (C6F5-) groups offer multiple fluoro groups to facilitate their replacement by the thiol groups from the host net. The inserted metalloporphyrin bridges impart to the metal-organic framework (MOF) host stable and recyclable activities for photocatalytic hydrogen production. We also disclose an improvement in synthetic methodology, in which BBr3 is used to simultaneously cleave the ester and benzyl thioether groups to more efficiently access thiol-equipped carboxylic acid building block.
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A novel 2D porous Zr(IV)-based metal-organic framework (USTS-7) was assembled from 2,5-bis[2-(methylthio)ethylthio]terephthalic acid and ZrCl4. USTS-7 retains its stability in water, strong acid, and base; moreover, it is highly luminescent and displays a remarkable selective sensing property toward Cr2O72- in aqueous solution with a very low detection limit.
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Finely dispersed Co(0) and CoO species were efficiently loaded into a stable metal-organic framework to impart catalytic activities to the porous solid. The metalation of the MOF host is facilitated by the dense arrays of accessible alkyne units that boost the alkyne-Co2(CO)8 interaction. The tetrakis(4-carboxylphenylethynyl)pyrene linker, with eight symmetrically backfolded alkyne side arms, features strong fluorescence and a dendritic Sierpinski shape. The resultant Zr(IV)-MOF features NU-901 topology (scu net, with rhombus channels) and breathing properties (e.g., the contracted (porous) phase reverts to the as-made phase upon contact with DMF (dimethylformamide)). The inserted Co2(CO)8 guests quickly react with air to form atomically dispersed CoO species (nondiffracting), and subsequent thermal treatment at 600 °C of the CoO-loaded solid generates an electrocatalyst for the oxygen evolution reaction (OER).
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Materials that demonstrate near-infrared (NIR) absorption and can simultaneously convert the electromagnetic irradiation into heat are promising for photothermal therapy. Traditionally, such a material is either pure inorganic, such as CuS, Ag2S, and carbon nanotube, or pure organic, such as polyaniline, polypyrrole, and conjugated polymers. Here we show that strong NIR photothermal effect can also be achieved in inorganic-organic hybrid coordination polymers (CPs) or metal-organic frameworks (MOFs). Our strategy is to construct CPs with inorganic Ag-S components that are interlinked by the organic ligands into a higher-dimensional hybrid network. Interestingly, the two resulting CPs, [Ag(Py-4-CSS)] n 1 and [Ag2(Py-4-CSS)(Py-4-CSSS)] n 2 (Py-4-CSS = pyridine-4-dithiocarboxylate; Py-4-CSSS = pyridine-4-perthiocarboxylate), show disparate structures due to the varied coordination mode of the pyridine group. For 1, the N atom coordinates to the Ag+ center and forms a two-dimensional square framework, while for 2, such a Ag-N bond is disconnected and forms only a one-dimensional structure. Interestingly, this difference leads to the distinct absorption properties in the NIR region. Under 800 nm radiation, the temperature of 1 can rise up to 24.5 °C in 3 min with photothermal conversion efficiency of 22.1%, which is about 2× that of pure inorganic Ag2S material and among the highest compared to various known inorganic materials, for example, Au nanoshells (13%), nanorods (21%), and Cu2- xSe nanocrystals (22%) irradiated with 800 nm light, while for 2, the NIR absorption is absent. This result first demonstrates that the inorganic-organic hybrid approach can be applied to construct superior NIR photothermal materials, but the control of the structure is vital. Here the coordinating nitrogen atoms in 1 are conceived to be critical in promoting the charge transfer between the dithiocarboxylate ligands. To elucidate the response to NIR irradiation of 1, we measured the heat capacity and dielectric constant of 1 and also performed density functional theory calculations. Significantly, the large dielectric constant and flat energy bands indicates 1 is much easier to be polarized and has a high electron effective mass. Thus, unlike the pure inorganic material, such as Ag2S, in which electron and hole can quantum mechanically combine to give off light, the joint-force of organic ligands in 1 effectively enhances polaronic recombination into heat.
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Excellent performance, real-time and low memory requirement are three vital requirements for target detection in high resolution marine radar system. Unfortunately, many current state-of-the-art methods merely achieve excellent performance when coping with highly complex scenes. In fact, a common problem is that real-time processing, low memory requirement and remarkable detection ability are difficult to coordinate. To address this issue, we propose a novel detection framework which bases its principle on sampling and spatiotemporal detection. The framework consists of two stages, coarse detection and fine detection. Sampling-based coarse detection is designed to guarantee the real-time processing and low memory requirements by locating the area where targets may exist in advance. Different from former detection methods, multi-scan video data are utilized. In the stage of fine detection, the candidate areas are grouped into three categories: single target, dense targets and sea clutter. Different approaches for processing the different categories are implemented to achieve excellent performance. The superiority of the proposed framework beyond state-of-the-art baselines is well substantiated in this work. Low memory requirement of the proposed framework was verified by theoretical analysis. Real-time processing capability was verified by the video data of two real scenarios. Synthetic data were tested to show the improvement in tracking performance by using the proposed detection framework.
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The problem of image segmentation can be reduced to the clustering of pixels in the intensity space. The traditional fuzzy c-means algorithm only uses pixel membership information and does not make full use of spatial information around the pixel, so it is not ideal for noise reduction. Therefore, this paper proposes a clustering algorithm based on spatial information to improve the anti-noise and accuracy of image segmentation. Firstly, the image is roughly clustered using the improved Lévy grey wolf optimization algorithm (LGWO) to obtain the initial clustering center. Secondly, the neighborhood and non-neighborhood information around the pixel is added into the target function as spatial information, the weight between the pixel information and non-neighborhood spatial information is adjusted by information entropy, and the traditional Euclidean distance is replaced by the improved distance measure. Finally, the objective function is optimized by the gradient descent method to segment the image correctly.
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Herein a strategy is reported for capturing and sensing iodine by strong I- â â â I2 â â â I- interaction, confined in a metal-organic framework, [Tb(Cu4 I4 )(ina)3 (DMF)] (1) (ina=isonicotinate). As revealed by single-crystal X-ray crystallography, the uptaken I2 molecules directly contact the {Cu4 I4 }n chains, virtually forming an electronically polarizable tetraiodide anion (I42- ) through strong I- â â â I2 â â â I- interaction. As such, a quasi-copper-iodide layer of {Cu4 I5 }n with semiconducting characteristics results, leading to a significant enhancement (Δσ =107 times) in electrical conductivity over the I2 -free 1. The effect observed is several orders of magnitude higher than those reported due to iodineâ â â aromatic interactions (Δσ =102 times) and by interactions between I2 and a redox-active metal centre (Δσ =104 times). The drastic enhancement in electrical conductivity was used to switch on/off an LED bulb, suggesting the possibility of electrically sensing I2 .
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Gut microbiota plays a crucial role in maintaining host homeostasis, impacting the progression and therapeutic outcomes of diseases, including inflammatory bowel disease, cancer, hepatic conditions, obesity, cardiovascular pathologies, and neurologic disorders, via immune, neural, and metabolic mechanisms. Hence, the gut microbiota is a promising target for disease therapy. The safety and precision of traditional microbiota regulation methods remain a challenge, which limits their widespread clinical application. This limitation has catalyzed a shift toward the development of multifunctional delivery systems that are predicated on microbiota modulation. Guided by bioinspired strategies, an extensive variety of naturally occurring materials and mechanisms have been emulated and harnessed for the construction of platforms aimed at the monitoring and modulation of gut microbiota. This review outlines the strategies and advantages of utilizing bioinspired principles in the design of gut microbiota intervention systems based on traditional regulation methods. Representative studies on the development of bioinspired therapeutic platforms are summarized, which are based on gut microbiota modulation to confer multiple pharmacological benefits for the synergistic management of diseases. The prospective avenues and inherent challenges associated with the adoption of bioinspired strategies in the refinement of gut microbiota modulation platforms are proposed to augment the efficacy of disease treatment.
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Microbioma Gastrointestinal , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Animais , Sistemas de Liberação de MedicamentosRESUMO
FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.
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Linhagem da Célula , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito , Neoplasias da Próstata , Fator de Transcrição AP-1 , Masculino , Humanos , Fator 3-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/genética , Linhagem Celular Tumoral , Linhagem da Célula/genética , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Animais , Cromatina/metabolismo , Cromatina/genética , Plasticidade Celular/genética , Reprogramação Celular/genética , Camundongos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Elementos Facilitadores Genéticos/genética , Transcrição GênicaRESUMO
One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Animais , Humanos , Masculino , Camundongos , Processamento Alternativo , Neoplasias Ósseas/secundário , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transcrição GênicaRESUMO
The lysine demethylase LSD1 (also called KDM1A) plays important roles in promoting multiple malignancies including both hematologic cancers and solid tumors. LSD1 targets histone and nonhistone proteins and can function as a transcriptional corepressor or coactivator. LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer and to regulate the AR cistrome via demethylation of its pioneer factor FOXA1. A deeper understanding of the key oncogenic programs targeted by LSD1 could help stratify prostate cancer patients for treatment with LSD1 inhibitors, which are currently under clinical investigation. In this study, we performed transcriptomic profiling in an array of castration-resistant prostate cancer (CRPC) xenograft models that are sensitive to LSD1 inhibitor treatment. Impaired tumor growth by LSD1 inhibition was attributed to significantly decreased MYC signaling, and MYC was found to be a consistent target of LSD1. Moreover, LSD1 formed a network with BRD4 and FOXA1 and was enriched at super-enhancer regions exhibiting liquid-liquid phase separation. Combining LSD1 inhibitors with BET inhibitors exhibited strong synergy in disrupting the activities of multiple drivers in CRPC, thereby inducing significant growth repression of tumors. Importantly, the combination treatment showed superior effects than either inhibitor alone in disrupting a subset of newly identified CRPC-specific super-enhancers. These results provide mechanistic and therapeutic insights for cotargeting two key epigenetic factors and could be rapidly translated in the clinic for CRPC patients. SIGNIFICANCE: LSD1 drives prostate cancer progression by activating super-enhancer-mediated oncogenic programs, which can be targeted with the combination of LSD1 and BRD4 inhibitors to suppress the growth of CRPC.
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Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Histona Desmetilases/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ciclo Celular/metabolismoRESUMO
Epigenetic reprogramming, mediated by genomic alterations and dysregulation of histone reader and writer proteins, plays a critical role in driving prostate cancer progression and treatment resistance. However, the specific function and regulation of EHMT1 (also known as GLP) and EHMT2 (also known as G9A), well-known histone 3 lysine 9 methyltransferases, in prostate cancer progression remain poorly understood. Through comprehensive investigations, we discovered that both EHMT1 and EHMT2 proteins have the ability to activate oncogenic transcription programs in prostate cancer cells. Silencing EHMT1/2 or targeting their enzymatic activity with small-molecule inhibitors can markedly decrease prostate cancer cell proliferation and metastasis in vitro and in vivo. In-depth analysis of posttranslational modifications of EHMT1 protein revealed the presence of methylation at lysine 450 and 451 residues in multiple prostate cancer models. Notably, we found that lysine 450 can be demethylated by LSD1. Strikingly, concurrent demethylation of both lysine residues resulted in a rapid and profound expansion of EHMT1's chromatin binding capacity, enabling EHMT1 to reprogram the transcription networks in prostate cancer cells and activate oncogenic signaling pathways. Overall, our studies provide valuable molecular insights into the activity and function of EHMT proteins during prostate cancer progression. Moreover, we propose that the dual-lysine demethylation of EHMT1 acts as a critical molecular switch, triggering the induction of oncogenic transcriptional reprogramming in prostate cancer cells. These findings highlight the potential of targeting EHMT1/2 and their demethylation processes as promising therapeutic strategies for combating prostate cancer progression and overcoming treatment resistance. Significance: In this study, we demonstrate that EHMT1 and EHMT2 proteins drive prostate cancer development by transcriptionally activating multiple oncogenic pathways. Mechanistically, the chromatin binding of EHMT1 is significantly expanded through demethylation of both lysine 450 and 451 residues, which can serve as a critical molecular switch to induce oncogenic transcriptional reprogramming in prostate cancer cells.
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Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Lisina , Histonas , Processos Neoplásicos , Neoplasias da Próstata/genética , Histona-Lisina N-Metiltransferase/genética , Cromatina , Desmetilação , Antígenos de HistocompatibilidadeRESUMO
With 2-COOH and 4-SH donors all packed onto the benzene ring, tetrasulfanyl terephthalic acid (TST) is a simple yet fully equipped ligand to move the field of metal-coordination materialsâit is now accomplished. The hard-soft carboxyl-thiol synergy is leveraged here in selectively bonding the carboxyl units to Zr(IV) ions to form the same cubic net of UiO-66 (this being based on the terephthalic linker)âwith the free-standing dithiolene units equipping the grid of ZrTST. The 3D network of ZrTST averages about 7.6 connections [as in Zr6O4(OH)4(C8H4O4S4)3.8], with the other 4.4 sealed by acetate ions. The ZrTST solid is stable in boiling water (it is formed in water/acetic acid/ethane dithiol) and remains ordered even above 300 °C. The thiol-enabled ZrTST (powder) takes up mercury from water with a high distribution coefficient Kd (e.g., 1.2 × 106 mL·g-1); it also shows proton conductivity (1.9 × 10-3 S·cm-1 at 90 °C and 90% relative humidity), which, most notably, increases to a highest value of 3.7 × 10-1 S·cm-1 after oxidizing the -SH into the -SO3H groups.
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Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.
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Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1 loss is also a critical event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa) induced by the androgen receptor (AR) signaling inhibition (ARSi). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of Rb inactivation on PCa progression and linage plasticity has been previously studied, there is a pressing need to fully understand underlying mechanisms and identify vulnerabilities that can be therapeutically targeted in Rb-deficient CRPC. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb-directly regulated genes and revealed that Rb has distinct binding sites and targets in CRPC with different genomic backgrounds. Significantly, we show that E2F1 chromatin binding and transcription activity in Rb-deficient CRPC are highly dependent on LSD1/KDM1A, and that Rb inactivation sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights into Rb activity in PCa progression and suggest that targeting LSD1 activity with small molecule inhibitors may be a potential treatment strategy to treat Rb-deficient CRPC.
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Neoplasias de Próstata Resistentes à Castração , Humanos , MasculinoRESUMO
A 3D polyimide is designed as an organic cathode for Li-ion batteries. Detailed characterization and DFT simulations demonstrate that the 3D polyimide undergoes the redox of naphthalenediimide radicals and the rigidity effect of the 3D structure contributes to the stability of the radical intermediates for high-performance organic batteries.
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Lithium-rich antiperovskites (LiRAPs) hold great promise to be the choice of solid-state electrolytes (SSEs) owing to their high ionic conductivity, low activation energy, and low cost. However, processing sheet-type solid-state Li metal batteries (SSLiB) with LiRAPs remains challenging due to the lack of robust techniques for battery processing. Herein, we propose a scalable slurry-based procedure to prepare a flexible composite electrolyte (CPE), in which LiRAP (e.g., Li2OHCl0.5Br0.5, LOCB) and nitrile butadiene rubber (NBR) serve as an active filler and as a polymer scaffold, respectively. The low-polar solvent helps to stabilize the LiRAP phase during slurry processing. It is found that the addition of LOCB into the NBR polymer enhances the Li ion conductivity for 2.3 times at 60°C and reduces the activation energy (max. 0.07 eV). The as-prepared LOCB/NBR CPE film exhibits an improved critical current of 0.4 mA cm-2 and can stably cycle for over 1000 h at 0.04 mA cm-2 under 60°C. In the SSLiB with the sheet-type configuration of LiFePO4(LFP)||LOCB/NBR CPE||Li, LFP exhibits a capacity of 137 mAh/g under 60 at 0.1°C. This work delivers an effective strategy for fabrication of LiRAP-based CPE film, advancing the LiRAP-family SSEs toward practical applications.