Targeted therapies with chemotherapeutic agents and immunotherapy with checkpoint inhibitors are among the systemic therapies recommended in the guidelines for clinicians to treat melanoma. Although there have been constant improvements in the treatment of melanoma, resistance to the established therapies continues to occur. Therefore, the purpose of this study was to explore the function of garcinol with regards to specific cancer properties such as proliferation and apoptosis. Garcinol, a natural compound isolated from the plant also known as mangosteen (Garcinia mangostana), is a newly discovered option for cancer treatment. Numerous pharmaceutical substances are derived from plants. For example, the derivates of camptothecin, extracted from the bark of the Chinese tree of happiness (Camptotheca acuminate), or paclitaxel, extracted from the bark of the Western yew tree (Taxus brevifolia), are used as anti-cancer drugs. Here, we show that garcinol reduced proliferation and induced apoptosis in melanoma cell lines. In addition, we found that those cells that are positive for the expression of the cell-cell adhesion molecule T-cadherin (CDH13) respond more sensitively to treatment with garcinol. After knock-down experiments with an siRNA pool against T-cadherin, the sensitivity to garcinol decreased and proliferation and anti-apoptotic behavior of the cells was restored. We conclude that patients who are T-cadherin-positive could especially benefit from a therapy with garcinol.

An observational cohort study of patients diagnosed with endometrial cancer (EC) stage IA G1, or atypical endometrial hyperplasia (AEH), undergoing organ-preserving treatment, was conducted.
OBJECTIVE: To determine CDO1, PITX2, and CDH13 gene methylation levels in early endometrial cancer and atypical hyperplasia specimens obtained before organ-preserving treatment in the patients with adequate response and with insufficient response to hormonal treatment.
METHODS: A total of 41 endometrial specimens obtained during diagnostic uterine curettage in women with EC (n = 28) and AEH (n = 13), willing to preserve reproductive function, were studied; 18 specimens of uterine cancer IA stage G1 from peri- and early postmenopausal women (comparison group) were included in the study. The control group included 18 endometrial specimens from healthy women obtained by diagnostic curettage for missed abortion and/or intrauterine adhesions. Methylation levels were analyzed using the modified MS-HRM method.
RESULTS: All 13 women with AEH had a complete response (CR) to medical treatment. In the group undergoing organ-preserving treatment for uterine cancer IA stage G1 (n = 28), 14 patients had a complete response (EC CR group) and 14 did not (EC non-CR group). It was found that all groups had statistically significant differences in CDO1 gene methylation levels compared to the control group (p < 0.001) except for the EC CR group (p = 0.21). The p-value for the difference between EC CR and EC non-CR groups was <0.001. The differences in PITX2 gene methylation levels between the control and study groups were also significantly different (p < 0.001), except for the AEH group (p = 0.21). For the difference between EC CR and EC non-CR groups, the p-value was 0.43. For CDH13 gene methylation levels, statistically significant differences were found between the control and EC non-CR groups (p < 0.001), and the control and EC comparison groups (p = 0.005). When comparing the EC CR group with EC non-CR group, the p-value for this gene was <0.001. The simultaneous assessment of CDO1 and CDH13 genes methylation allowed for an accurate distinction between EC CR and EC non-CR groups (AUC = 0.96).
CONCLUSIONS: The assessment of CDO1 and CDH13 gene methylation in endometrial specimens from patients with endometrial cancer (IA stage G1), scheduled for medical treatment, can predict the treatment outcome.

T-cadherin is a regulator of blood vessel remodeling and angiogenesis, involved in adiponectin-mediated protective effects in the cardiovascular system and in skeletal muscles. GWAS study has previously demonstrated a SNP in the Cdh13 gene to be associated with hypertension. However, the role of T-cadherin in regulating blood pressure has not been experimentally elucidated. Herein, we generated Cdh13∆Exon3 mice lacking exon 3 in the Cdh13 gene and described their phenotype. Cdh13∆Exon3 mice exhibited normal gross morphology, life expectancy, and breeding capacity. Meanwhile, their body weight was considerably lower than of WT mice. When running on a treadmill, the time spent running and the distance covered by Cdh13∆Exon3 mice was similar to that of WT. The resting blood pressure in Cdh13∆Exon3 mice was slightly higher than in WT, however, upon intensive physical training their systolic blood pressure was significantly elevated. While adiponectin content in the myocardium of Cdh13∆Exon3 and WT mice was within the same range, adiponectin plasma level was 4.37-fold higher in Cdh13∆Exon3 mice. Moreover, intensive physical training augmented the AMPK phosphorylation in the skeletal muscles and myocardium of Cdh13∆Exon3 mice as compared to WT. Our data highlight a critically important role of T-cadherin in regulation of blood pressure and stamina in mice, and may shed light on the pathogenesis of hypertension.

OBJECTIVE: To investigate DNA methylation of specific gene promoters in endometrial hyperplasia compared to normal endometrial tissue.
METHODS: To search for epigenetic events, methylation-specific multiplex ligation-dependent probe amplification was employed to compare the methylation status of 64 tissue samples with atypical endometrial hyperplasia, 60 tissue samples with endometrial hyperplasia without atypia, and 40 control tissue samples with normal endometrium.
RESULTS: Differences in DNA methylation among the groups were found in PTEN, CDH13, and MSH6 promoters (PTEN: atypical hyperplasia 32%, benign hyperplasia 6.8%, normal endometrium 10%; P=0.004; CDH13: atypical hyperplasia, 50%; benign hyperplasia, 43%; normal endometrium 8.1%; P=0.003; MSH6 atypical hyperplasia 84%, benign hyperplasia, 62%; normal endometrium, 52%; P=0.008.) Higher rates of CDH13 promoter methylation were identified in the groups with both forms of endometrial hyperplasia when compared to the control group (atypical hyperplasia, P=0.003, benign hyperplasia, P=0.0002). A higher rate of DNA methylation of the PTEN and MSH6 promoters was observed in samples with atypical endometrial hyperplasia than in samples with benign endometrial hyperplasia (PTEN: P=0.02; MSH6: P=0.01) and samples with normal endometrial tissue (PTEN, P=0.04; MSH6, P=0.006).
CONCLUSIONS: DNA methylation of CDH13, PTEN, and MSH6 appear to be involved in the development of endometrial hyperplasia.

CDH13 is an atypical member of the cadherin family and is closely related to the clinicopathological factors and prognosis of many types of cancer. However, the role of CDH13 in clear cell renal cell carcinoma (ccRCC) remains unknown. Therefore, we comprehensively analyzed the expression level, diagnostic efficacy, clinical significance, prognostic value, immune infiltration, methylation status, genetic alteration, and biological functions of CDH13 in ccRCC patients. The results showed that CDH13 was significantly upregulated in ccRCC and strongly correlated with better survival, lower cancer stages, and lower tumor grades of ccRCC patients. Additionally, the immune infiltration analysis indicated that CDH13 might play a crucial role in regulating the tumor microenvironment of ccRCC. The results of methylation analysis showed that the epigenetic status of CDH13 was altered, and the prognosis of ccRCC patients was related not only to DNA methylation but also to m6A modification of CDH13. Finally, the results based on clinical samples further elucidated the expression pattern of CDH13 in ccRCC. In conclusion, CDH13 might be a novel prognostic biomarker and therapeutic target for patients with ccRCC. And our study provides new insights into the potential molecular changes and strategies for the treatment of ccRCC.

CDH13 encodes T-cadherin, which is expressed in the vasculature and cardiac myocytes and is the receptor for hexameric and high-molecular-weight adiponectin. The CDH13 region is the most pivotal locus associated with adiponectin level. Mediation analysis is a method to explore the effect of a third variable, it is assumed that the magnitude of the relationship between the independent and dependent variables will be reduced by statistical adjustment for a third variable. In addition, mediation can further occur in the case when the mediator acts as a pathway-suppressor variable that means a suppression effect may be suggested if the statistical removal of a mediation effect could increase the magnitude of the relationship between the independent and dependent variables. Here, we aimed to explore the suppression effect in a genome-wide association study, and investigate possible mechanisms that may link adiponectin to CDH13 variants and high-density lipoprotein cholesterol (HDL-C). Genome-wide association data for adiponectin and HDL-C were accessible for 2349 Taiwan-biobank participants. The mediation analysis was conducted with the CDH13 lead single nucleotide polymorphism (SNP) rs4783244. The cloned constructs of CDH13 haplotypes (GG and TT) identified from the rs4783244 G/T and rs12051272 G/T SNPs were transiently expressed in HEK293T cells and investigated using the luciferase reporter assay. Genome-wide association analysis showed that HDL-C is significantly associated with variants in CDH13 after adjusting for the adiponectin level. The lead SNP rs4783244 was significantly associated with lower adiponectin levels and exhibited a suppression effect on HDL-C when adiponectin was included as a third factor in the mediation analysis. Luciferase reporter assay results further demonstrated that the GG haplotype increased enhancer activity, whereas the haplotype TT significantly reduced the activity of this enhancer. We present the first evidence of the suppressive role of adiponectin in the genome-wide association between CDH13 and HDL-C. CDH13 may increase the HDL-C levels, and its expression is suppressed by adiponectin.

The cell-cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.

Psychosis is a highly heritable and heterogeneous psychiatric condition. Its genetic architecture is thought to be the result of the joint effect of common and rare variants. Families with high prevalence are an interesting approach to shed light on the rare variant\'s contribution without the need of collecting large cohorts. To unravel the genomic architecture of a family enriched for psychosis, with four affected individuals, we applied a system genomic approach based on karyotyping, genotyping by whole-exome sequencing to search for rare single nucleotide variants (SNVs) and SNP array to search for copy-number variants (CNVs). We identified a rare non-synonymous variant, g.39914279 C > G, in the MACF1 gene, segregating with psychosis. Rare variants in the MACF1 gene have been previously detected in SCZ patients. Besides, two rare CNVs, DUP3p26.3 and DUP16q23.3, were also identified in the family affecting relevant genes (CNTN6 and CDH13, respectively). We hypothesize that the co-segregation of these duplications with the rare variant g.39914279 C > G of MACF1 gene precipitated with schizophrenia and schizoaffective disorder.

The transplantation of muscle progenitor cells (MuPCs) differentiated from human induced pluripotent stem cells (hiPSCs) is a promising approach for treating skeletal muscle diseases such as Duchenne muscular dystrophy (DMD). However, proper purification of the MuPCs before transplantation is essential for clinical application. Here, by using MYF5 hiPSC reporter lines, we identified two markers for myogenic cell purification: CDH13, which purified most of the myogenic cells, and FGFR4, which purified a subset of MuPCs. Cells purified with each of the markers showed high efficiency for regeneration after transplantation and contributed to the restoration of dystrophin expression in DMD-immunodeficient model mice. Moreover, we found that MYF5 regulates CDH13 expression by binding to the promoter regions. These findings suggest that FGFR4 and CDH13 are strong candidates for the purification of hiPSC-derived MuPCs for therapeutical application.

Genetic factors play a major role in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). In this study, we aimed to investigate the relationship between the CDH13 (rs6565113, rs11150556) and LPHN3 (rs6551665, rs6858066, rs1947274, rs2345039) gene polymorphisms and ADHD. We also sought to examine possible relationships between these polymorphisms and the clinical course and treatment response in ADHD. A total of 120 patients (79% boys), aged 6 to 18 years, newly diagnosed (medication-naïve) with ADHD according to the DSM-5 and a group of 126 controls (74% girls) were enrolled in the study. We examined the association between the aforementioned polymorphisms and ADHD. Univariate and multivariate logistic regression analysis were used to evaluate factors influencing the treatment response of ADHD. A significant difference was found between ADHD and control groups in terms of genotype distribution of the LPHN3 rs6551665 and rs1947274 polymorphisms. The results also showed that having the GG genotype of rs6551665 and CC genotype of rs1947274 of the LPHN3 gene was associated with risk for ADHD, and this relationship was more prominent in male participants. In the multivariate logistic regression model established with variables shown to have a significant relationship with treatment response, the presence of the GG genotype of the LPHN3 rs6551665 polymorphism and high severity of ADHD assessed by CGI-S were associated with poor response to treatment. This study is the first study to investigate the relationship between ADHD and these polymorphisms among Turkish adolescents. Our results imply that the LPHN3 rs6551665 and rs1947274 polymorphisms have a significant effect on ADHD in a Turkish population, and support previous observations that the presence of the GG genotype of the LPHN3 rs6551665 polymorphism may be associated with poor response to treatment in ADHD.