Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit.

In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.

Association study of the functional variants of the GLIS3 gene with risk of knee osteoarthritis.

INTRODUCTION/OBJECTIVES: Osteoarthritis (OA) ranks the most common joint disorder and the leading cause of disability. Growing evidence has revealed that OA has a strong genetic background, except for aging and obesity. The aim of this study is to determine the associations between potential functional variants of the GLIS3 and GLIS3-AS1 gene and risk of knee OA among a Chinese population. METHODS: In this case-control study with 810 knee OA cases and 900 healthy controls, seven selected functional SNPs of the GLIS3 and GLIS3-AS1 gene were evaluated. RESULTS: We found minor alleles of rs10116772 (OR: 0.80, 95% CI: 0.69-0.92, P = 0.002), rs7045410 (OR: 0.74, 95% CI: 0.61-0.92, P = 0.005), and rs7032713 (OR: 0.76, 95% CI: 0.63-0.93, P = 0.006) were significantly associated with decreased risk of knee OA. Results of the dominant and recessive model, stratified analyses using Kellgren-Lawrence (KL) grading presented that the significant associations were not materially changed. Haplotype analysis indicated that haplotype CGT (OR: 0.66, 95% CI: 0.46-0.96, P = 0.031) and ATT (OR: 0.76, 95% CI: 0.6-0.95, P = 0.017) were significantly associated with decreased risk of knee OA. Further, they were also significantly associated with lower expression level of GLIS3, as well as higher expression level of GLIS3-AS1 in the articular cartilage specimens. Genotype-tissue expression (GTEX) data also validated that minor alleles of rs7045410 and rs7032713 were significantly associated with higher expression level of GLIS3-AS1 in thyroid and pituitary tissues (P < 0.001). CONCLUSIONS: These findings revealed the essential role of genetic variants of the GLIS3 and GLIS3-AS1 gene in the occurrence of knee OA together. Key Point • Functional variants of the GLIS3 and GLIS3-AS1 gene were significantly associated with decreased risk of knee OA.