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.

Abdominal-B regulates structure and development of the Harmonia axyridis cremaster.

The ladybird Harmonia axyridis is an insect that exhibits pupal attachment to plants, which facilitates development and environmental adaptation. The cremaster is highly specialized for this behavior. However, the underlying molecular regulation of the cremaster remains unclear; therefore, we performed experiments to investigate the transcriptional regulation of cremaster development. First, we examined the morphological structure of the cremaster to reveal its function in pupal attachment of H. axyridis. Next, we analyzed the Hox gene Ha-Abd-B using RNA interference (RNAi) to determine its function in regulating cremaster formation; Ha-Abd-B up-regulation promoted effective pupal attachment, whereas successful RNAi caused severe down-regulation of this gene, and pupae were unable to attach. Furthermore, successful RNAi and subsequent Ha-Abd-B down-regulation caused phenotypic changes in cremaster structure, including its complete disappearance from some individuals. Finally, we observed unique development of the cremaster and dynamic expression of Ha-Abd-B during pre-pupal development; consequently, we hypothesized that there was specific pre-pupal development of the cremaster. Overall, based on these results, the specialized cremasteric structure located on the posterior side of H. axyridis was determined to be a key organ for pupal attachment. Cremaster identification in H. axyridis is regulated by Ha-Abd-B and exhibits preferential development. Pupal attachment of H. axyridis reveals an environmental adaptation of this species; thus, this study and future molecular studies will help determine the role of Hox genes in regulation of insect attachment and further our understanding of the multiple functions of Hox genes.

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.

Superficially Similar Adaptation Within One Species Exhibits Similar Morphological Specialization but Different Physiological Regulations and Origins.

Animals have developed numerous strategies to contend with environmental pressures. We observed that the same adaptation strategy may be used repeatedly by one species in response to a certain environmental challenge. The ladybird Harmonia axyridis displays thermal phenotypic plasticity at different developmental stages. It is unknown whether these superficially similar temperature-induced specializations share similar physiological mechanisms. We performed various experiments to clarify the differences and similarities between these processes. We examined changes in the numbers and sizes of melanic spots in pupae and adults, and confirmed similar patterns for both. The dopamine pathway controls pigmentation levels at both developmental stages of H. axyridis. However, the aspartate-ß-alanine pathway controls spot size and number only in the pupae. An upstream regulation analysis revealed the roles of Hox genes and elytral veins in pupal and adult spot formation. Both the pupae and the adults exhibited similar morphological responses to temperatures. However, they occurred in different body parts and were regulated by different pathways. These phenotypic adaptations are indicative of an effective thermoregulatory system in H. axyridis and explains how insects contend with certain environmental pressure based on various control mechanisms.