O-linked-β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC.

Background: In recent years, many studies have indicated that tissue inhibitor of metalloproteinases-1 (TIMP-1) protein has a close relationship with prognosis in cancer patients. However, other studies have not drawn the same conclusion. Methods: The current systematic review and meta-analysis was conducted to assess the prognostic effects of TIMP1 in cancer patients. Eleven studies were involved in the analysis, including four that evaluated breast cancer, two that evaluated colon cancer, and one each that evaluated epithelial ovarian cancer, lung cancer, gastric cancer, hepatocellular cancer, and laryngeal squamous cell cancer. Results: Results indicate that increased TIMP1 protein levels yield worse overall survival (OS) (hazard ratio (HR) = 1.58, 95% confidence intervals (CI) 1.25-2.01). Subgroup analysis by tumor type showed that high expression of TIMP-1 was associated with poor OS in colon cancer (HR = 2.40, 95% CI 1.35-4.25), rather than in breast cancer (HR = 1.21, 95% CI 0.83-1.74). Subgroup analysis by ethnicity showed that high expression of TIMP-1 was associated with poor OS in Asians (HR = 2.24, 95% CI 1.64-3.06) and Caucasians (HR = 1.32, 95% CI 1.02-1.75). Conclusion: In summary, TIMP-1 is a poor prognostic maker for solid tumors.

BACKGROUND:Acute graft-versus-host disease (aGVHD) is a medical complication which may result in significant morbidity and mortality after transplantation. The aim of this study investigated the therapeutic effect and underlying mechanism of 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in the treatment of aGVHD.METHOD:An aGVHD model was built by transferring splenocytes of B6 mice into B6D2F1 mice. 1α,25(OH)2D3 was added to evaluate the protective function to aGVHD; the phenotype and cytokine expression profile of spleen cells from the aGVHD model were determined using flow cytometry 2 weeks after the model is established.RESULT:Administration of 1α,25(OH)2D3 significantly slowed aGVHD progression and improved survival of B6D2F1 recipients of grafted B6 splenocytes. 1α,25(OH)2D3 treatment also resulted in an increased number of CD4+Foxp3+ regulatory T cells (Tregs) but decreased the number of CD4+IL-4+ cells. In vitro analysis demonstrated that 1α,25(OH)2D3 directly increased forkhead box P3 (Foxp3) and IL-10 expression and enhanced the function of induced Tregs (iTregs).CONCLUSIONS:This analysis indicated that the effect of 1α,25(OH)2D3 is mediated in part by improving the number of Tregs. 1α,25(OH)2D3 administration thus represents a viable approach for treating aGVHD.