Voluntary Exercise Attenuates Tumor Growth in a Preclinical Model of Castration-Resistant Prostate Cancer.

Purpose: To examine the effects of voluntary exercise training on tumor growth and explore the underlying intratumoral molecular pathways and processes responsible for the beneficial effects of VWR on tumor initiation and progression in a mouse model of Castration-Resistant Prostate Cancer (CRPC). Methods: Male immunodeficient mice (SCID) were castrated and subcutaneously inoculated with human CWR-22RV1 cancer cells to construct CRPC xenograft model before randomly assigned to either voluntary wheel running (VWR) or sedentary (SED) group (n=6/group). After three weeks, tumor tissues were collected. Tumor size was measured and calculated. mRNA expression of markers of DNA replication, Androgen Receptor (AR) signaling, and mitochondrial dynamics was determined by RT-PCR. Protein expression of mitochondrial content and dynamics was determined by western blotting. Finally, RNA-sequencing analysis was performed in the tumor tissues. Results: Voluntary wheel running resulted in smaller tumor volume at the initial stage and attenuated tumor progression throughout the time course (P < 0.05). The reduction of tumor volume in VWR group was coincided with lower mRNA expression of DNA replication markers ( MCM2 , MCM6 , and MCM7 ), AR signaling ( ELOVL5 and FKBP5 ) and regulatory proteins of mitochondrial fission (Drp1 and Fis1) and fusion (MFN1 and OPA1) when compared to the SED group (P<0.05). More importantly, RNA sequencing data further revealed that pathways related to pathways related to angiogenesis, extracellular matrix formation and endothelial cell proliferation were downregulated. Conclusions: Three weeks of VWR was effective in delaying tumor initiation and progression, which coincided with reduced transcription of DNA replication, AR signaling targets and mitochondrial dynamics. We further identified reduced molecular pathways/processes related to angiogenesis that may be responsible for the delayed tumor initiation and progression by VWR.

FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer.

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.

Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.

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.

SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1.

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.

Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2.

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.

Early assessment of chemotherapeutic response in hepatocellular carcinoma based on serum surface-enhanced Raman spectroscopy.

In clinical practice, the transcatheter arterial chemoembolization (TACE) has been widely accepted as the first option for non-surgical hepatocellular carcinoma (HCC) treatment. However, patients with HCC often suffer from poor response to TACE therapy. This can be prevented if the chemotherapeutic response can be early and accurately assessed, which is essential to guide timely and rational management. In this study, the serum SERS technique was for the first time investigated as a potential prognostic tool for early assessment of HCC chemotherapeutic response. According to the SERS spectral analysis results, it is newly found that not only the absolute circulating nucleic acids and collagen levels in pre-therapeutic serum but also the changes in circulating nucleic acids and amino acids between pre-therapeutic and post-therapeutic serum are expected to be potential serum markers for HCC prognosis. By further applying chemometrics methods to establish prognostic models, excellent prognostic accuracies were achieved within only 3 days after TACE therapy. Thus, the proposed method is expected to provide guidance on timely and rational management of HCC to improve its survival rate.

Developing Highly Tough, Heat-Resistant Blend Thermosets Based on Silicon-Containing Arylacetylene: A Material Genome Approach.

Silicon-containing arylacetylene (PSA) resins exhibit excellent heat resistance, yet their brittleness limits the applications. We proposed using acetylene-terminated polyimides (ATPI) as an additive to enhance the toughness of the PSA resins and maintain excellent heat resistance. A material genome approach (MGA) was first established for designing and screening the acetylene-terminated polyimides, and a polyimide named ATPI was filtered out by using this MGA. The ATPI was synthesized and blended with PSA resins to improve the toughness of the thermosets. Influences of the added ATPI contents and prepolymerization temperature on the properties were examined. The result shows that the blend resin can resist high temperature and bear excellent mechanical properties. The molecular dynamics simulations were carried out to understand the mechanism behind the improvement of toughness. The present work provides a method for the rapid design and screening of high-performance polymeric materials.