Valproic acid (VPA) has anticancer, anti-inflammatory, and epigenetic effects. The study aimed to determine the expression of carcinogenesis-related SLC5A8, SLC12A2, SLC12A5, CDH1, and CDH2 in adult glioblastoma U87 MG and T98G cells and the effects of 0.5 mM, 0.75 mM, and 1.5 mM doses of VPA. RNA gene expression was determined by RT-PCR. GAPDH was used as a control. U87 and T98G control cells do not express SLC5A8 or CDH1. SLC12A5 was expressed in U87 control but not in T98G control cells. The SLC12A2 expression in the U87 control was significantly lower than in the T98G control. T98G control cells showed significantly higher CDH2 expression than U87 control cells. VPA treatment did not affect SLC12A2 expression in U87 cells, whereas treatment dose-dependently increased SLC12A2 expression in T98G cells. Treatment with 1.5 mM VPA induced SLC5A8 expression in U87 cells, while treatment of T98G cells with VPA did not affect SLC5A8 expression. Treatment of U87 cells with VPA significantly increased SLC12A5 expression. VPA increases CDH1 expression depending on the VPA dose. CDH2 expression was significantly increased only in the U87 1.5 mM VPA group. Tested VPA doses significantly increased CDH2 expression in T98G cells. When approaching treatment tactics, assessing the cell\'s sensitivity to the agent is essential.

UNASSIGNED: Arrhythmogenic cardiomyopathy/dysplasia (ACM) is an inheritable heart disease closely related to gene variations induced heart fibrofatty replacement, which increases the risk of arrhythmia events and even sudden cardiac death. In this study, we reported a 10-year-old patient with a novel mutation diagnosed with ACM.
UNASSIGNED: We present the case of a 10-year-old patient admitted with recurrent palpitation, whose electrocardiogram suggested the existence of right ventricle origin premature ventricular contractions and ε wave. Furthermore, echocardiography showed an enlarged right ventricle corrected to a body surface area of 29.57 mm/m2. The diagnosis of ACM was clear. Further gene sequencing revealed a novel heterozygous missense mutation of CDH2 (cadherin-2) c.547C > G (p. P183A) that potentially increases ACM risk by affecting adherens junctions of the intercalated discs.
UNASSIGNED: This is the first case of CDH2 mutation (c.547C > G, p. P183A) related ACM in the Chinese population. Compared to previously reported mutations inducing ACM by affecting desmosome function, the newly reported CDH2 variation revealed a novel potential mechanism that induces ACM by disturbing cell-cell adhesion.

UNASSIGNED: Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.
UNASSIGNED: The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant.
UNASSIGNED: Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing.
UNASSIGNED: One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected.
UNASSIGNED: A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations.
UNASSIGNED: A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.

MSX1 is an important member of the muscle segment homeobox gene (Msh) family and acts as a transcription factor to regulate tissue plasticity, yet its role in goat endometrium remodeling remains elusive. In this study, an immunohistochemical analysis showed that MSX1 was mainly expressed in the luminal and glandular epithelium of goat uterus, and the MSX1 expression was upregulated in pregnancy at days 15 and 18 compared with pregnancy at day 5. In order to explore its function, goat endometrial epithelial cells (gEECs) were treated with 17 β-estrogen (E2), progesterone (P4), and/or interferon-tau (IFNτ), which were used to mimic the physiological environment of early pregnancy. The results showed that MSX1 was significantly upregulated with E2- and P4-alone treatment, or their combined treatment, and IFNτ further enhanced its expression. The spheroid attachment and PGE2/PGF2α ratio were downregulated by the suppression of MSX1. The combination of E2, P4, and IFNτ treatment induced the plasma membrane transformation (PMT) of gEECs, which mainly showed the upregulation of N-cadherin (CDH2) and concomitant downregulation of the polarity-related genes (ZO-1, α-PKC, Par3, Lgl2, and SCRIB). The knockdown of MSX1 partly hindered the PMT induced by E2, P4, and IFNτ treatment, while the upregulation of CDH2 and the downregulation of the partly polarity-related genes were significantly enhanced when MSX1 was overexpressed. Moreover, MSX1 regulated the CDH2 expression by activating the endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) pathway. Collectively, these results suggest that MSX1 was involved in the PMT of the gEECs through the ER stress-mediated UPR pathway, which affects endometrial adhesion and secretion function.

Pediatric high-grade gliomas (pHGGs) are heterogeneous, diffuse, and highly infiltrative tumors with dismal prognosis. Aberrant post-translational histone modifications with elevated histone 3 lysine trimethylation (H3K9me3) have been recently implicated in pHGGs\' pathology, conferring to tumor heterogeneity. The present study investigates the potential involvement of H3K9me3 methyltransferase SETDB1 in the cellular function, progression, and clinical significance of pHGG. The bioinformatic analysis detected SETDB1 enrichment in pediatric gliomas compared to the normal brain, as well as positive and negative correlations with a proneural and mesenchymal signature, respectively. In our cohort of pHGGs, SETDB1 expression was significantly increased compared to pLGG and normal brain tissue and correlated with p53 expression, as well as reduced patients\' survival. In accordance, H3K9me3 levels were also elevated in pHGG compared to the normal brain and were associated with worse patient survival. Gene silencing of SETDB1 in two patient-derived pHGG cell lines showed a significant reduction in cell viability followed by reduced cell proliferation and increased apoptosis. SETDB1 silencing further reduced cell migration of pHGG cells and the expression of the mesenchymal markers N-cadherin and vimentin. mRNA analysis of epithelial-mesenchymal transition (EMT) markers upon SETDB1 silencing showed a reduction in SNAI1 levels and downregulation of CDH2 along with the EMT regulator gene MARCKS. In addition, SETDB1 silencing significantly increased the bivalent tumor suppressor gene SLC17A7 mRNA levels in both cell lines, indicating its implication in the oncogenic process.Altogether, our findings demonstrate a predominant oncogenic role of SETDB1 in pHGG which along with elevated H3K9me3 levels correlate significantly to tumor progression and inferior patients\' survival. There is evidence that targeting SETDB1 may effectively inhibit pHGG progression, providing a novel insight into the therapeutic strategies for pediatric gliomas. KEY MESSAGES: SETDB1 gene expression is enriched in pHGG compared to normal brain. SETDB1 expression is increased in pHGG tissues and associates with reduced patients\' survival. Gene silencing of SETDB1 reduces cell viability and migration. SETDB1 silencing affects mesenchymal markers expression. SETDB1 silencing upregulates SLC17A7 levels. SETDB1 has an oncogenic role in pHGG.

BACKGROUND: RNA N6-methyladenosine (m6A) is involved in mammalian spermatogenesis. In both germ cells and Leydig cells, ALKBH5 regulates spermatogenesis and androgen synthesis in an m6A-dependent manner. However, it is unclear whether ALKBH5 plays a role in testicular Sertoli cells, which constitute the blood-testis barrier (BTB) through cell junctions between adjacent Sertoli cells.
METHODS: ALKBH5 expression in the testes of humans and mice was detected by immunohistochemical staining and immunofluorescence staining. BTB integrity was evaluated by BTB assay. m6A-seq was performed to screen for BTB-related molecules regulated by ALKBH5. m6A immunoprecipitation-quantitative real-time polymerase chain reaction (qPCR), RNA immunoprecipitation-qPCR, western blot, coimmunoprecipitation, and polysome fractionation-qPCR analyses were performed to explore the mechanisms of ALKBH5 in BTB. Transmission electron microscopy was applied to observe the BTB ultrastructure.
RESULTS: ALKBH5 in Sertoli cells is related to the integrity of the BTB. Subsequently, the m6A level on Cdh2 mRNA, encoding a structural protein N-cadherin in the BTB, was found to be regulated by ALKBH5. IGF2BP1/2/3 complexes and YTHDF1 promoted Cdh2 mRNA translation. In addition, we found that basal endoplasmic specialization, in which N-cadherin is a main structural protein, was severely disordered in the testes of Alkbh5-knockout mice.
CONCLUSIONS: Our study revealed that ALKBH5 regulates BTB integrity via basal endoplasmic specialization by affecting Cdh2 mRNA translation.

CDH2 belongs to the classic cadherin family of Ca2+-dependent cell adhesion molecules with a meticulously described dual role in cell adhesion and β-catenin signaling. During CNS development, CDH2 is involved in a wide range of processes including maintenance of neuroepithelial integrity, neural tube closure (neurulation), confinement of radial glia progenitor cells (RGPCs) to the ventricular zone and maintaining their proliferation-differentiation balance, postmitotic neural precursor migration, axon guidance, synaptic development and maintenance. In the past few years, direct and indirect evidence linked CDH2 to various neurological diseases, and in this review, we summarize recent developments regarding CDH2 function and its involvement in pathological alterations of the CNS.

In poikilothermic animals, the distinct acclimatization ability of different organs has been previously addressed, while the tissue-specific role of cold stress in early development is largely unknown. In this study, we discovered that despite its role in delaying embryonic development, mild cold stress (22°C) does not disturb multiple-organ progenitor specification, but does give rise to organ left-right (LR) patterning defects. Regarding the mechanism, the data showed that mild cold stress downregulated the expression of cell-adhesion genes cdh1 and cdh2 during gastrulation, especially in dorsal forerunner cells (DFCs), which partially disturbed the clustering movement of DFCs, Kupffer\'s vesicle (KV) morphogenesis, and ciliogenesis. As a result, the defects of KV/cilia disrupted asymmetric nodal signaling and subsequent heart and liver LR patterning. In conclusion, our data novelly identified that, in early development, DFCs are more sensitive to mild cold stress, and mild cold stress repressed the expression of cell adhesion-related gene cdh1 and cdh2. This role partially disturbed the clustering movement of DFCs, which resulted in defective KV/cilia development and sequential organ LR patterning defects.

To identify regulatory ncRNA molecules that can cause differential expression of CDH2 in intervertebral disc degeneration (IDD) and explore whether there are other ways to affect the progression of IDD.
A primary culture of human nucleus pulposus (NP) cells was established and identified by immunofluorescence. An in vitro IDD model was constructed by compressing human NP cells, and the MTT assay was used to measure cell viability. Changes in the ncRNA group were analysed by RNA-seq. The expression levels of hsa_circ_7042, CDH2, and miR-369-3p were detected by qPCR. Cell apoptosis, senescence, and extracellular matrix (ECM) metabolism were detected by flow cytometry, β-galactosidase staining, and Western blotting. hsa_circ_7042, miR-369-3p, and bone morphogenetic protein 2 (BMP2) were verified by luciferase and RNA immunoprecipitation (RIP) analyses. The PI3K/Akt pathway was validated by transfection of BMP2 siRNA. Furthermore, a mouse model of lumbar spine instability was constructed. circ_7042 adenovirus was packaged and injected into the intervertebral discs of mice, and the influence of circ_7042 overexpression on intervertebral disc degeneration was determined.
Western blotting, qPCR, and flow cytometry analyses confirmed that overexpression of circ_7042 could downregulate miR-369-3p and upregulate the expression of CDH2 and BMP2 in IDD cell and animal models. Additionally, the levels of apoptotic and senescent cells decreased, and ECM degradation decreased. The PI3K/Akt pathway was significantly activated after circ_7042 was overexpressed. The injection of circ_7042-overexpressing adenovirus effectively reduced ECM degradation and the level of apoptosis in NP tissue.
circ_7042 could upregulate the expression of CDH2 and BMP2 by absorbing miR-369-3p, and the increased BMP2 activated the PI3K/Akt pathway, thus improving IDD.