The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer.

BACKGROUND: The transcription factor GATA4 is pivotal in cancer development but is often silenced through mechanisms like DNA methylation and histone modifications. This silencing suppresses the transcriptional activity of GATA4, disrupting its normal functions and promoting cancer progression. However, the precise molecular mechanisms and implications of GATA4 silencing in tumorigenesis remain unclear. Here, we aim to elucidate the mechanisms underlying GATA4 silencing and explore its role in breast cancer progression and its potential as a therapeutic target. METHODS: The GATA4-breast cancer prognosis link was explored via bioinformatics analyses, with GATA4 expression measured in breast tissues. Functional gain/loss experiments were performed to gauge GATA4's impact on breast cancer cell malignancy. GATA4-PRC2 complex interaction was analyzed using silver staining and mass spectrometry. Chromatin immunoprecipitation, coupled with high-throughput sequencing, was used to identify GATA4-regulated downstream target genes. The in vitro findings were validated in an in situ breast cancer xenograft mouse model. RESULTS: GATA4 mutation and different breast cancer subtypes were correlated, suggesting its involvement in disease progression. GATA4 suppressed cell proliferation, invasion, and migration while inducing apoptosis and senescence in breast cancer cells. The GATA4-PRC2 complex interaction silenced GATA4 expression, which altered the regulation of FAS, a GATA4 downstream gene. In vivo experiments verified that GATA4 inhibits tumor growth, suggesting its regulatory function in tumorigenesis. CONCLUSIONS: This comprehensive study highlights the epigenetic regulation of GATA4 and its impact on breast cancer development, highlighting the PRC2-GATA4-FAS pathway as a potential target for therapeutic interventions in breast cancers.

Enhancer of zeste homolog 2 facilitates phenotypic transition of vascular smooth muscle cells leading to aortic aneurysm/dissection.

Thoracic aortic aneurysms (TAAs) are a major cause of death owing to weaker blood vessel walls and higher rupture rates in affected individuals. Vascular smooth muscle cells (VSMCs) are the predominant cell type within the aortic wall and their dysregulation may contribute to TAA progression. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is involved in several pathological processes; however, the biological functions and mechanisms underlying VSMC phenotype transition and vascular intimal hyperplasia remain unclear. The present study aimed to determine the involvement of EZH2 in mediating VSMC function in the development of TAAs. The expression of EZH2 was revealed to be elevated in patients with thoracic aortic dissection and TAA mouse model through western blotting and reverse transcription-quantitative PCR experiments. Subsequently, a mouse model was established using ß-aminopropionitrile. In vitro, EdU labeling, Transwell assay, wound healing assay and hematoxylin-eosin staining revealed that knocking down the Ezh2 gene could reduce the proliferation, invasion, migration, and calcification of mouse primary aortic smooth muscle cells. Flow cytometry analysis found that EZH2 deficiency increased cell apoptosis. Depletion of Ezh2 in mouse primary aortic VSMCs promoted the transformation of VSMCs from a synthetic to a contractile phenotype. Using RNA-sequencing analysis, it was demonstrated that Ezh2 regulated a group of genes, including integrin ß3 (Itgb3), which are critically involved in the extracellular matrix signaling pathway. qChIP found Ezh2 occupies the Itgb3 promoter, thereby suppressing the expression of Itgb3. Ezh2 promotes the invasion and calcification of VSMCs, and this promoting effect is partially reversed by co-knocking down Itgb3. In conclusion, the present study identified a previously unrecognized EZH2-ITGB3 regulatory axis and thus provides novel mechanistic insights into the pathophysiological function of EZH2. EZH2 may thus serve as a potential target for the management of TAAs.

Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.

Biomimetic Boroxine-Based Multifunctional Thermosets via One-Pot Synthesis.

Boroxine-based thermosets with remarkable mechanical tunability, self-healing ability, recyclability, and adhesive strength are of significant importance in various applications. However, complex multistep reactions are often required to prepare such thermosets. Herein, a facile one-pot approach to synthesize boroxine-based malleable thermosets is proposed. Random copolymers with pendant boronic acid groups were synthesized from alkenyl monomers containing boronic acids [4-vinylphenylboronic acid (4-VPBA), 3-vinylphenylboronic acid, or 3-acrylamidophenylboronic acid] and octadecanoxy polyethylene glycol methacrylate. Then, the as-prepared copolymers were cured to form thermosets with boroxine bonds. The tensile strengths of the thermosets were tailored to range from 9.3 to 27.5 MPa by increasing the concentration of 4-VPBA. Moreover, because of the reversible nature of dynamic boroxine bonds (transformation between boroxines and boronic acids) induced by water, the thermosets exhibit remarkable self-healing efficiency (up to 99%), tunable mechanical properties, and excellent recyclability. Additionally, the thermosets also demonstrate superior adhesive strength (as high as 73.9 MPa) on different substrates.

Multifunctional Glycerol-Water Hydrogel for Biomimetic Human Skin with Resistance Memory Function.

Biomimetic human skinlike materials with preferably self-healing ability, high sensitivity for external stimuli, and good adhesiveness against diverse substrates under a wide range of temperatures are of great importance in various applications such as wearable devices, human-motion devices, and soft robotics. However, most of the reported biomimetic human skinlike materials lack memory function, i.e., they cannot memorize the external stimuli once the stimuli disappear. This drawback hinders their applications in mimicking the human skin in real world. Here, a polyacrylamide/Au@polydopamine glycerol-water (GW) hydrogel has been designed to address this challenge. The as-prepared GW hydrogel exhibits a fast self-healing efficiency and good adhesiveness against diverse substrates under a wide range of temperatures (from -15 to 37 °C). Additionally, our GW hydrogel also possesses good perceived ability for external stimuli and subtle/large human motions. Most importantly, resistance memory function has been realized based on our GW hydrogel. These outstanding properties make it potentially significant in mimicking the human skin in real world.

Self-healable poly(acrylic acid-co-maleic acid)/glycerol/boron nitride nanosheet composite hydrogels at low temperature with enhanced mechanical properties and water retention.

Many living tissues possess excellent mechanical properties and water retention which enable them to self-heal at room temperature even below the freezing temperature of water. To mimic the unique features of living tissue, a poly(acrylic acid-co-maleic acid) composite hydrogel with enhanced mechanical properties and remarkable water retention was fabricated under accessible conditions. The hydrogel is functionalized by amino group modified boron nitride nanosheets (BNNS-NH2)/glycerol and exhibits self-healing abilities at low temperature. The self-healing process occurs through the re-establishing of hydrogen bonds and metal coordination interactions at the damaged surfaces. Its anti-freezing abilities enable the hydrogel to self-heal at -15 °C, and the self-healing efficiency based on tensile strength reaches up to ∼70%. Moreover, glycerol also endows the hydrogel with long-lasting water retention, which remains a water content of ∼99 wt% for more than 30 days. Meanwhile, the simultaneous introduction of BNNS-NH2 and glycerol significantly improved the mechanical properties of the hydrogel, which displays great stretchability (∼474%), tensile strength (∼151.3 kPa), stiffness (Young's modulus of ∼62.75 kPa) and toughness (∼355.13 kJ m-3). It is anticipated that these novel hydrogels will develop many fields and be exploited for new applications in extensive external environments.

Fabrication of Poly(acrylic acid)/Boron Nitride Composite Hydrogels with Excellent Mechanical Properties and Rapid Self-Healing Through Hierarchically Physical Interactions.

Many living tissues possess excellent mechanical properties and self-healing ability. To mimic these living tissues, a series of novel composite hydrogels, poly(acrylic acid)/surface-modified boron nitride nanosheets (PAA/BNNS-NH2) were fabricated simply through hierarchically physical interactions: molecular-scale metal coordination interaction between -COOH of PAA and Fe3+ and nanoscale H-bond between -COOH of PAA and -NH2 of BNNS-NH2. The composite hydrogels exhibit both excellent mechanical properties (including enhanced fracture stress, elongation, toughness, Young's modulus, and dissipated energy) and rapid healing ability without any external stimulus. Especially, the B0.5P70 (the hydrogel with BNNS concentration of 0.5 mg mL- 1, the water content of 70 wt%) exhibits a fracture stress of ~ 1311 kPa and toughness of ~ 4.7 MJ m- 3, almost ~ 3 times and ~ 8 times to B0P70, respectively. The excellent properties, combined with the simple preparation method, endow these composite hydrogels with potential applications.

Boron Nitride Nanosheets/PNIPAM Hydrogels with Improved Thermo-Responsive Performance.

Thermo-responsive hydrogel is an important smart material. However, its slow thermal response rate limits the scope of its applications. Boron nitride nanosheet-reinforced thermos-responsive hydrogels, which can be controlled by heating, were fabricated by in situ polymerization of N-isopropylacrylamide in the presence of boron nitride nanosheets. The hydrogels exhibit excellent thermo-responsiveness and much enhanced thermal response rate than that of pure poly(N-isopropylacrylamide) hydrogels. Interestingly, the hydrogels can be driven to move in aqueous solution by heating. Importantly, the composite hydrogel is hydrophilic at a temperature below lower critical solution temperature (LCST), while it is hydrophobic at a temperature above LCST. Therefore, it can be used for quick absorption and release of dyes and oils from water. All these properties demonstrate the potential of hydrogel composites for water purification and treatment.