ABSTRACT
Histone demethylase KDM7A regulates neuronal differentiation and development in mammals. In this study, we found that KDM7A was also required for breast cancer stem cells (BCSCs) maintenance. Silencing KDM7A significantly reduced the BCSCs population and mamosphere formation in vitro, and inhibited breast tumor growth in vivo. Restoring KDM7A expression rescued the defect in stem cell maintenance. Our mechanism analysis suggested that KDM7A upregulated the stemness-associated factors KLF4 and c-MYC for BCSCs maintenance. In addition, KDM7A knockdown promoted apoptosis through decreasing BCL2 expression and BAD phosphorylation in breast cancer (BrCa). Furthermore, restoring KDM7A and BCL2 expression rescued apoptosis inhibition in breast cancer, suggesting that KDM7A inhibited apoptosis by upregulating the BCL2 level in breast cancer. In conclusion, KDM7A promotes cancer stem cell maintenance and apoptosis inhibition in breast cancer.
Subject(s)
Apoptosis/genetics , Breast Neoplasms/pathology , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Neoplastic Stem Cells/pathology , Adenocarcinoma/pathology , Animals , Breast Neoplasms/genetics , Cell Proliferation/genetics , Female , Humans , Kruppel-Like Factor 4 , Mice , Mice, Nude , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Interference , RNA, Small Interfering/genetics , Spheroids, Cellular , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , bcl-Associated Death Protein/metabolismABSTRACT
Exosomal microRNAs (miRNAs) are important biomarkers for clinical diagnosis and disease treatment monitoring. However, most approaches for exosomal miRNA detection are time-consuming, laborious, and expensive. Herein, we report a virus-mimicking fusogenic vesicle (Vir-FV) that enables rapid, efficient, and high-throughput detection of exosomal miRNAs within 2â h. Fusogenic proteins on Vir-FVs can specifically target the sialic-acid-containing receptors on exosomes, inducing efficient fusion of Vir-FVs and exosomes. Upon vesicle content mixing, the molecular beacons encapsulated in Vir-FVs specifically hybridize with the target miRNAs in the exosomes, generating fluorescence. Combined with flow cytometry, the Vir-FVs can not only detect exosomal miRNAs but also distinguish tumor exosomes from normal exosomes by sensing the tumor-related miRNAs, paving the way towards the rapid and efficient detection of exosomal miRNAs for diagnosis and prognosis prediction of diseases.
Subject(s)
Exosomes/metabolism , MicroRNAs/metabolism , HumansABSTRACT
The difficulty in identifying tumor tissues from healthy brain tissues is a major challenge for the accurate resection of glioma in clinical practice. Many efforts have been made to develop targeting probes to precisely visualize and resect glioma. However, most of these probes are hindered by non-degradation, intolerable toxicity, complicated and costly preparation procedures. In this work, we report an ανß3 integrin-targeted near-infrared (NIR) fluorescent probe DP-RGD for detection of glioma. Considering its well-defined structure, good biodegradability, and biocompatibility, dendritic polylysine (DP) is selected as the carrier which is conjugated with a glioma-targeting ligand c(RGDyK) and NIR fluorescent dye IR783. The diameter of the targeted probe DP-RGD can be well controlled in a range of 10-20 nm. Cytotoxicity and histological analysis demonstrated that the probe possesses good biocompatibility. NIR fluorescent imaging studies indicated that this probe possessed high tumor targeting efficiency and precisely visualized the glioma xenograft with a high tumor to normal tissue signal ratio. Above all, the ανß3 integrin-targeted probe DP-RGD shows great promise for noninvasively and precisely visualizing glioma and holds the possibility for NIR fluorescent imaging-guided glioma resection.
Subject(s)
Dendrimers/chemistry , Glioma/diagnostic imaging , Integrin alphaVbeta3/chemistry , Polylysine/chemistry , Animals , HumansABSTRACT
H3K4me3 and H3K36me2 histone demethylase KDM2B is an epigenetic regulatory factor involved in cell proliferation in numerous cells including breast cancer cells, however, the regulatory mechanism of KDM2B in cell proliferation of breast cancer cells, specifically in triple negative breast cancer (TNBC), remains largely unknown. In this study, we showed that higher expression level of KDM2B was associated with poor prognosis in TNBC. Using cell proliferation assay, we found that KDM2B promoted TNBC cell proliferation by suppressing the transcription of the cell cycle inhibitors p15INK4B, p16INK4A, and p57KIP2. Chromatin immunoprecipitation assay results showed that KDM2B bound to the promoters of these genes and thereby reduced the H3K4me3 and H3K36me2 levels, leading to the suppression of gene transcription in a histone demethylation activity-dependent manner. Silencing of p15INK4B, p16INK4A, and p57KIP2 in TNBC cells was shown to restore the promoting effect of KDM2B on TNBC cell proliferation. The present study reveals a novel cell regulatory mechanism through which KDM2B promotes TNBC cell proliferation by binding to the promoters of p15INK4B, p16INK4A, and p57KIP2, which reduces H3K4me3 and H3K36me2 levels to suppress gene transcription.