Biofilms are polymicrobial, with diverse bacterial species competing for limited space and nutrients. Under healthy conditions, the different species in biofilms maintain an ecological balance. This balance can be disturbed by environmental factors and interspecies interactions. These perturbations can enable dominant growth of certain species, leading to disease. To model clinically relevant interspecies antagonism, we studied three well-characterized and closely related oral species, Streptococcus gordonii, Streptococcus sanguinis, and cariogenic Streptococcus mutans. S. sanguinis and S. gordonii used oxygen availability and the differential production of hydrogen peroxide (H 2 O 2 ) to compete effectively against S. mutans. Interspecies antagonism was influenced by glucose with reduced production of H 2 O 2 . Furthermore, aerobic conditions stimulated the competence system and the expression of the bacteriocin mutacin IV of S. mutans, as well as the H 2 O 2 -dependent release of heterologous DNA from mixed cultures of S. sanguinis and S. gordonii. These data provide new insights into ecological factors that determine the outcome of competition between pioneer colonizing oral streptococci and the survival mechanisms of S. mutans in the oral biofilm.
SIRT1 is a class III histone deacetylase and plays important roles in aging, obesity, and cancer (1, 2). Dramatic up-regulation of SIRT1 has been observed in various cancers including breast, prostate, and ovarian cancers, implicating a role for SIRT1 in tumorigenesis (3-5). SIRT1 functions by deacetylating histone (e.g. H3-Lys9 and H4-Lys16) and non-histone proteins (e.g. p300 and Ku70) in an NAD ϩ -dependent manner, thus modifying gene expression and modulating protein activity (1, 6). Previous studies have illustrated several mechanisms of SIRT1-dependent gene silencing in addition to histone deacetylation. It was shown that at sites of DNA damage, SIRT1 recruits DNA methyltransferases (DNMTs) 2 to promoter regions leading to hypermethylation and potential silencing of tumor suppressor genes (e.g. E-cadherin) (7). It is also known that SIRT1 facilitates transcriptional repression of tumor suppressor genes by modulating histone methyltransferase SUV39h1, the key enzyme responsible for histone H3 methylation (H3-Lys9-me3) in regions of heterochromatin (8). SIRT1 induction of tumor suppressor gene silencing promotes the initiation and progression of tumors as well as drug resistance (1, 9, 10). Studies from our laboratory and others show that inhibition of SIRT1 by pharmacological inhibitors or genetic depletion reduces estrogen-dependent signaling pathways in breast cancer cells (11,12). The inhibition of SIRT1 in breast and prostate cancer cell lines has resulted in acetylation of p53 and subsequent growth arrest and apoptosis, while not affecting viability of several non-cancer epithelial cell lines (13,14). Although several inhibitors of sirtuins have been described (reviewed in Ref. 15), and the potential value that SIRT1 inhibition may possess for cancer therapy has been recognized, there are no ongoing clinical trials of SIRT1 inhibitors for cancer therapy because of serious concerns, e.g. stability and toxicity. These deficiencies have lead to the search for new molecules that regulate SIRT1 expression. SIRT1 expression can be mediated at the transcriptional level and several mechanisms involved in dysregulation of SIRT1 in cancer cells have been proposed (16). Tumor suppressors p53 and HIC1 (hypermethylated in cancer 1) can bind to the SIRT1 promoter and form a complex with SIRT1, leading to inhibition of SIRT1 transcription (17,18). In cancer cells, inactivation of these tumor suppressor genes by genetic or epigenetic mechanisms leads to up-regulation of SIRT1 transcription. However, this is not the sole mechanism for overexpression of SIRT1 in tumors. For example, the RNA binding protein HuR, a potential oncoprotein, stabilizes SIRT1 mRNA through 3Ј-untranslated region (3Ј-UTR) interactions leading to elevated SIRT1 levels (19). This suggests that the 3Ј-UTR of SIRT1 mRNA may also be important in governing SIRT1 expression in tumors.
Triple-negative (ER-, HER2-, PR-) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of micRoRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 down-regulation in TNBC was examined. Overexpression of the long non-coding RNA, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth suppressive activity in some breast cancers; however, the current data in TNBC indicates that miR-145 does not impact proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145 regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and impacts cell-cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs. Implications The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival.
NF-E2-related factor 2 (Nrf2) is an important transcription factor that activates the expression of cellular detoxifying enzymes. Nrf2 expression is largely regulated through the association of Nrf2 with Kelch-like ECH-associated protein 1 (Keap1), which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression. Until now, a regulatory role for microRNAs (miRs) in controlling Keap1 gene expression had not been characterized. By using miR array-based screening, we observed miR200a silencing in breast cancer cells and demonstrated that upon re-expression, miR-200a targets the Keap1 3-untranslated region (3-UTR), leading to Keap1 mRNA degradation. Loss of this regulatory mechanism may contribute to the dysregulation of Nrf2 activity in breast cancer. Previously, we have identified epigenetic repression of miR-200a in breast cancer cells. Here, we find that treatment with epigenetic therapy, the histone deacetylase inhibitor suberoylanilide hydroxamic acid, restored miR-200a expression and reduced Keap1 levels. This reduction in Keap1 levels corresponded with Nrf2 nuclear translocation and activation of Nrf2-dependent NAD(P)H-quinone oxidoreductase 1 (NQO1) gene transcription. Moreover, we found that Nrf2 activation inhibited the anchorage-independent growth of breast cancer cells. Finally, our in vitro observations were confirmed in a model of carcinogen-induced mammary hyperplasia in vivo. In conclusion, our study demonstrates that miR-200a regulates the Keap1/Nrf2 pathway in mammary epithelium, and we find that epigenetic therapy can restore miR200a regulation of Keap1 expression, therefore reactivating the Nrf2-dependent antioxidant pathway in breast cancer.
Extracellular DNA (eDNA) is produced by several bacterial species and appears to contribute to biofilm development and cell-cell adhesion. We present data showing that the oral commensals Streptococcus sanguinis and Streptococcus gordonii release DNA in a process induced by pyruvate oxidase-dependent production of hydrogen peroxide (H 2 O 2 ). Surprisingly, S. sanguinis and S. gordonii cell integrity appears unaffected by conditions that cause autolysis in other eDNA-producing bacteria. Exogenous H 2 O 2 causes release of DNA from S. sanguinis and S. gordonii but does not result in obvious lysis of cells. Under DNA-releasing conditions, cell walls appear functionally intact and ribosomes are retained over time. During DNA release, intracellular RNA and ATP are not coreleased. Hence, the release mechanism appears to be highly specific for DNA. Release of DNA without detectable autolysis is suggested to be an adaptation to the competitive oral biofilm environment, where autolysis could create open spaces for competitors to invade. Since eDNA promotes cell-to-cell adhesion, release appears to support oral biofilm formation and facilitates exchange of genetic material among competent strains.The release of bacterial DNA into the environment is of recent interest since this polymer is now recognized to stabilize cell-to-cell adherence and biofilm architecture (1,35,37). Treatment of extracellular DNA (eDNA) with DNase results in reduced intercellular stickiness, consistent with an adhesive function for eDNA. Furthermore, eDNA from Neisseria meningitis appears to have sufficient structural integrity to transform competent strains (11), indicating chromosomal origin. Since the abundance of eDNA is influenced by growth conditions, DNA release can also be regulated (40).DNA release is typically a consequence of cell lysis. Linked to DNA release, genetic transformation is the natural ability of competent bacterial species to take up DNA from the environment (13,34,42). During competence development, Streptococcus pneumoniae DNA is released by lysis of a subpopulation of cells (30,42). Cell lysis and DNA release are controlled in a cell density-dependent signal transduction process. The S. pneumoniae comX regulon, carrying late competence genes, also includes the murein hydrolase genes lytA and cbpD (19,42). Murein hydrolases digest structural components of the peptidoglycan, contributing to remodeling, recycling, and daughter cell separation. Furthermore, murein hydrolases trigger autolytic cell wall digestion, leading to release of DNA and other cellular content into the environment (36). The autolysis of bacterial cells as part of a regulated death program seems to be an important source for eDNA in diverse species, including Staphylococcus aureus (4, 36, 37), Staphylococcus epidermidis (35), Enterococcus faecalis (44), and Pseudomonas aeruginosa (1). In these species, the eDNA contributes to biofilm formation as a component of the extracellular biofilm matrix (35,37,44).Unlike for cell lysis-dependent release, the oral...
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