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.

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1.

Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, an urgent need exists for the development of predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-ß-catenin pathway, contributes to the poor prognosis of OSCC. Herein, we aimed to explore the correlation between LEF1 and histone lysine demethylase 4 A (KDM4A). Results show that the KDM4A complex is recruited by LEF1 and specifically binds the LATS2 promoter region, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. We also established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth, and our findings show that cells stably suppressing LEF1 or KDM4A have markedly decreased tumour-initiating capacity. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.

Functional Study of TMEM163 Gene Variants Associated with Hypomyelination Leukodystrophy.

Hypomyelinating leukodystrophies (HLDs) are a rare group of heterogeneously genetic disorders characterized by persistent deficit of myelin observed on magnetic resonance imaging (MRI). To identify a new disease-associated gene of HLD, trio-based whole exome sequencing was performed for unexplained patients with HLD. Functional studies were performed to confirm the phenotypic effect of candidate protein variants. Two de novo heterozygous variants, c.227T>G p.(L76R) or c.227T>C p.(L76P) in TMEM163 were identified in two unrelated HLD patients. TMEM163 protein is a zinc efflux transporter localized within the plasma membrane, lysosomes, early endosomes, and other vesicular compartments. It has not been associated with hypomyelination. Functional zinc flux assays in HeLa cells stably-expressing TMEM163 protein variants, L76R and L76P, revealed distinct attenuation or enhancement of zinc efflux, respectively. Experiments using a zebrafish model with knockdown of tmem163a and tmem163b (morphants) showed that loss of tmem163 causes dysplasia of the larvae, locomotor disability and myelin deficit. Expression of human wild type TMEM163 mRNAs in morphants rescues the phenotype, while the TMEM163 L76P and L76R mutants aggravated the condition. Moreover, poor proliferation, elevated apoptosis of oligodendrocytes, and reduced oligodendrocytes and neurons were also observed in zebrafish morphants. Our findings suggest an unappreciated role for TMEM163 protein in myelin development and add TMEM163 to a growing list of genes associated with hypomyelination leukodystrophy.

Anti-cancer efficacy of biotinylated chitosan nanoparticles in liver cancer.

The present study investigated the synthesis of biotinylated chitosan (Bio-CS) from chitosan using a nanomaterial skeleton with biotin and the successful targeting of the formulation in liver cancer cells. Bio-CS was validated by fourier transformed infrared spectroscopy and hydrogen-1 nuclear magnetic resonance spectroscopy. Bio-CS and plasmid DNA were used to construct Bio-CS/plasmid DNA nanoparticles according to the optimal molar ratio of 1:1 and the optimal pH-value of 5.5. Under these conditions, the parameters mean particle size, potential, encapsulation rate and drug loading, were 82.9 nm, +21.8 mV, 85.7% and 35.4%, respectively. Bio-CS exhibited an apparent liver cancer targeting effect in vitro and in vivo, as demonstrated by confocal laser scanning, green fluorescent protein transfection, and in vivo imaging assays. In addition, the Bio-CS/plasmid DNA nanoparticles significantly increased the survival period of the orthotropic liver cancer mouse model compared with the plasmid DNA, with no apparent side effects on the cells. Bio-CS nanomaterials stimulated an immune response in hepatoma cells via increased expression of GM-CSF, IL-21 and Rae-1 markers. The data suggest that Bio-CS increased the inhibition of liver cancer cell proliferation in vitro and the activation of the cellular immunity in vivo.

Synthesis of galactosylated chitosan/5-fluorouracil nanoparticles and its characteristics, in vitro and in vivo release studies.

Biodegradable polymer nanoparticle drug delivery systems are characterized by targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability, and lowered side effects; these drug delivery systems are widely used for delivery of cytotoxic agents. The galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticle is a nanomaterial made by coupling GC, a polymer known to have the advantages described above, and 5-FU. We found that when 5-FU and GC were mixed at the mass ratio of 10:1, the nanoparticle reached a maximum encapsulation efficiency of 81.82% ± 5.32%, with a drug loading of 6.12% ± 1.36%, a particle size of 35.19 ± 9.50 nm, and a Zeta potential of +10.34 ± 1.43 mV. The GC/5-FU nanoparticle is a sustained release system, whose anticancer effects were shown to be dose and time dependent, with a higher cytotoxicity to hepatic cancer than to other cell types. The distribution of GC/5-FU in vivo revealed the greatest accumulation in the hepatic cancer tissues, with an 8.69-, 23.35-, 79.96-, and 85.15-fold increase when compared to normal liver tissue, kidney, heart and blood, respectively, suggesting that the hepatic cell was the target of the nanoparticles. In vivo experiments showed that GC/5-FU can significantly inhibit tumor growth in an orthotropic liver cancer mouse model. GC/5-FU treatment can significantly lower the tumor weight and increase the survival time of mice when compared to 5-FU treatment alone. Flow cytometry revealed that compared to 5-FU, GC/5-FU caused higher rates of G0-G1 arrest and apoptosis in hepatic cancer cells.