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FAK is a tyrosine kinase overexpressed in cancer cells and plays an important role in the progression of tumors to a malignant phenotype. Except for its typical role as a cytoplasmic kinase downstream of integrin and growth factor receptor signaling, related studies have shown new aspects of the roles of FAK in the nucleus. FAK can promote p53 degradation through ubiquitination, leading to cancer cell growth and proliferation. FAK can also regulate GATA4 and IL-33 expression, resulting in reduced inflammatory responses and immune escape. These findings establish a new model of FAK from the cytoplasm to the nucleus. Activated FAK binds to transcription factors and regulates gene expression. Inactive FAK synergizes with different E3 ligases to promote the turnover of transcription factors by enhancing ubiquitination. In the tumor microenvironment, nuclear FAK can regulate the formation of new blood vessels, affecting the tumor blood supply. This article reviews the roles of nuclear FAK in regulating gene expression. In addition, the use of FAK inhibitors to target nuclear FAK functions will also be emphasized.

a b s t r a c tSilver nanoparticles (nanosilver, AgNPs) have been shown to induce toxicity in vitro and in vivo; however, the molecular bases underlying the detrimental effects have not been thoroughly understood. Although there are numerous studies on its genotoxicity, only a few studies have investigated the epigenetic changes, even less on the changes of histone modifications by AgNPs. In the current study, we probed the AgNP-induced alterations to histone methylation that could be responsible for globin reduction in erythroid cells. AgNP treatment caused a significant reduction of global methylation level for histone 3 (H3) in erythroid MEL cells at sublethal concentrations, devoid of oxidative stress. The ChIP-PCR analyses demonstrated that methylation of H3 at lysine (Lys) 4 (H3K4) and Lys 79 (H3K79) on the b-globin locus was greatly reduced. The reduction in methylation could be attributed to decreased histone methyltransferase DOT-1L and MLL levels as well as the direct binding between AgNPs to H3/H4 that provide steric hindrance to prevent methylation as predicted by the all-atom molecular dynamics simulations. This direct interaction was further proved by AgNP-mediated pull-down assay and immunoprecipitation assay. These changes, together with decreased RNA polymerase II activity and chromatin binding at this locus, resulted in decreased hemoglobin production. By contrast, Ag ion-treated cells showed no alterations in histone methylation level. Taken together, these results showed a novel finding in which AgNPs could alter the methylation status of histone. Our study therefore opens a new avenue to study the biological effects of AgNPs at sublethal concentrations from the perspective of epigenetic mechanisms.

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Salvianolic acids, the most effective and abundant compounds extracted from Salvia miltiorrhiza (Danshen), are well known for its good anti-oxidative activity. Danshen has been extensively used as a traditional medicine to treat cardiovascular-related diseases in China and other Asian countries for hundreds of years. Recently, more and more studies have demonstrated that salvianolic acids also have a good effect on the alleviation of fibrosis disease and the treatment of cancer. In vivo and in vitro experiments have demonstrated that salvianolic acids can modulate signal transduction within fibroblasts and cancer cells. It is discovered that the cancer treatment of salvianolic acids is not only because salvianolic acids promote the apoptosis of cancer cells, but also due to the inhibition of cancer-associated epithelial-mesenchymal transition processes. In this article, we review a variety of studies focusing on the comprehensive roles of salvianolic acids in the treatment of fibrosis disease and cancer. These perspectives on the therapeutic potential of salvianolic acids highlight the importance of these compounds, which could be the novel and attractive drugs for fibrosis disease and cancer.

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