Previous studies have reported aberrant expression of the miR-183-96-182 cluster in a variety of tumors, which indicates its' diagnostic or prognostic value. However, a key characteristic of the miR-183-96-182 cluster is its varied expression levels, and pleomorphic functional roles in different tumors or under different conditions. In most tumor types, the cluster is highly expressed and promotes tumorigenesis, cancer progression and metastasis; yet tumor suppressive effects have also been reported in some tumors. In the present study, we discuss the upstream regulators and the downstream target genes of miR-183-96-182 cluster, and highlight the dysregulation and functional roles of this cluster in various tumor cells. Newer insights summarized in this review will help readers understand the different facets of the miR-183-96-182 cluster in cancer development and progression.
PurposePolydopamine-coated branched Au–Ag nanoparticles (Au–Ag@PDA NPs) exhibit good structural stability, biocompatibility, and photothermal performance, along with potential anticancer efficacy. Here, we investigated the cytotoxicity of Au–Ag@PDA NPs against human bladder cancer cells (T24 cells) in vitro and in vivo, as well as the underlying molecular mechanisms of photothermal therapy-induced T24 cell death.Materials and methodsT24 cells were treated with different doses of Au–Ag@PDA NPs followed by 808 nm laser irradiation, and the effects on cell proliferation, cell cycle, apoptosis, and autophagy were analyzed. To confirm the mechanisms of inhibition, real-time PCR and Western blot analysis were used to evaluate markers of cell cycle, apoptosis, autophagy, and the AKT/ERK signaling pathway. Moreover, we evaluated the effects of the treatment on mitochondrial membrane potential and ROS generation to confirm the underlying mechanisms of inhibition. Finally, we tested the T24 tumor inhibitory effects of Au–Ag@PDA NPs plus laser irradiation in vivo using a xenograft mouse model.ResultsAu–Ag@PDA NPs, with appropriate laser irradiation, dramatically inhibited the proliferation of T24 cells, altered the cell cycle distribution by increasing the proportion of cells in the S phase, induced cell apoptosis by activating the mitochondria-mediated intrinsic pathway, and triggered a robust autophagy response in T24 cells. Moreover, Au–Ag@PDA NPs decreased the expression of phosphorylated AKT and ERK and promoted the production of ROS that function upstream of apoptosis and autophagy. In addition, Au–Ag@PDA NP-mediated photothermolysis also significantly suppressed tumor growth in vivo.ConclusionThis preclinical study can provide a mechanistic basis for Au–Ag@PDA NP-mediated photothermal therapy toward promotion of this method in the clinical treatment of bladder cancer.
Oleanolic acid (OA) is a natural compound from plants with anti-tumor activities. However, the mechanism of the inhibitory effect of OA on cell cycle progression has not been completely explored. We employed several lung carcinoma cell lines to investigate the cell cycle-related molecular pathway affected by OA. The data revealed that OA suppressed the proliferation of lung cancer cells in both dose- and time-dependent manners, along with an increase in miR-122 abundance. The suppression of miR-122 abolished the effect of OA on lung cancer cells. CCNG1 and MEF2D, two putative miR-122 targets, were found to be downregulated by OA treatment. Restoring their expression counteracted the effect of OA on lung carcinoma cells. OA was further shown to induce the expression of miR-122-regulating transcriptional factors in lung cancer cells. Collectively, OA induced cell cycle arrest in lung cancer cells through miR-122/Cyclin G1/MEF2D pathway. This finding may contribute to the understanding of the molecular mechanism of OA's anti-tumor activity.
hMOF (MYST1), a histone acetyltransferase (HAT), forms at least two distinct multiprotein complexes in human cells. The male specific lethal (MSL) HAT complex plays a key role in dosage compensation in Drosophila and is responsible for histone H4K16ac in vivo. We and others previously described a second hMOF-containing HAT complex, the non-specific lethal (NSL) HAT complex. The NSL complex has a broader substrate specificity, can acetylate H4 on K16, K5, and K8. The WD (tryptophan-aspartate) repeat domain 5 (WDR5) and host cell factor 1 (HCF1) are shared among members of the MLL/SET (mixed-lineage leukemia/set-domain containing) family of histone H3K4 methyltransferase complexes. The presence of these shared subunits raises the possibility that there are functional links between these complexes and the histone modifications they catalyze; however, the degree to which NSL and MLL/SET influence one another's activities remains unclear. Here, we present evidence from biochemical assays and knockdown/overexpression approaches arguing that the NSL HAT promotes histone H3K4me2 by MLL/SET complexes by an acetylation-dependent mechanism. In genomic experiments, we identified a set of genes including ANKRD2, that are affected by knockdown of both NSL and MLL/SET subunits, suggested they are co-regulated by NSL and MLL/SET complexes. In ChIP assays, we observe that depletion of the NSL subunits hMOF or NSL1 resulted in a significant reduction of both H4K16ac and H3K4me2 in the vicinity of the ANKRD2 transcriptional start site proximal region. However, depletion of RbBP5 (a core component of MLL/SET complexes) only reduced H3K4me2 marks, but not H4K16ac in the same region of ANKRD2, consistent with the idea that NSL acts upstream of MLL/SET to regulate H3K4me2 at certain promoters, suggesting coordination between NSL and MLL/SET complexes is involved in transcriptional regulation of certain genes. Taken together, our results suggest a crosstalk between the NSL and MLL/SET complexes in cells.
Human males absent on the first (hMOF), a human ortholog of the Drosophila MOF protein, is responsible for histone H4 lysine 16 (H4K16) acetylation in human cells. The depletion of hMOF leads to a global reduction in histone H4K16 acetylation in human cells, genomic instability, cell cycle defects, reduced transcription of certain genes, defective DNA damage repair and early embryonic lethality. Studies have shown that abnormal hMOF gene expression is involved in a number of primary cancers. The present study examined the involvement of hMOF expression and histone H4K16 acetylation in clinically diagnosed primary ovarian cancer tissues. Clinically diagnosed frozen primary ovarian cancer tissues were used for polymerase chain reaction (PCR), quantitative PCR (qPCR), western blotting and immunohistochemical staining approaches. A PCR analysis of mRNA expression in 47 samples revealed a downregulation of hMOF mRNA in 81% of patients, whereas only 13% of patients demonstrated upregulation. qPCR was used to validate the frequent downregulation of hMOF expression in the primary ovarian cancer tissues. As expected, the analysis of hMOF expression in 57 samples revealed that hMOF mRNA expression was significantly downregulated (>2-fold decrease) in 65% of patients, while a <2-fold reduction of hMOF was observed in 10.5% of patients. Furthermore, the expression of hMOF-regulated human leukocyte antigen (HLA) complex 5, (HCP5), was also found to be downregulated in >87% of patients with a decrease in hMOF. hMOF and its regulated gene, HCP5, are frequently downregulated in human ovarian cancer, suggesting that hMOF may be involved in the pathogenesis of the disease.
Histone post-translational modification heritably regulates gene expression involved in most cellular biological processes. Experimental studies suggest that alteration of histone modifications affects gene expression by changing chromatin structure, causing various cellular responses to environmental influences. Arsenic (As), a naturally occurring element and environmental pollutant, is an established human carcinogen. Recently, increasing evidence suggests that As-mediated epigenetic mechanisms may be involved in its toxicity and carcinogenicity, but how this occurs is still unclear. Here we present evidence that suggests As-induced global histone H4K16 acetylation (H4K16ac) partly due to the direct physical interaction between As and histone acetyltransferase (HAT) hMOF (human male absent on first) protein, leading to the loss of hMOF HAT activity. Our data show that decreased global H4K16ac and increased deacetyltransferase HDAC4 expression occurred in arsenic trioxide (As2O3)-exposed HeLa or HEK293T cells. However, depletion of HDAC4 did not affect global H4K16ac, and it could not raise H4K16ac in cells exposed to As2O3, suggesting that HDAC4 might not directly be involved in histone H4K16 de-acetylation. Using As-immobilized agarose, we confirmed that As binds directly to hMOF, and that this interaction was competitively inhibited by free As2O3. Also, the direct interaction of As and C2CH zinc finger peptide was verified by MAIDI-TOF mass and UV absorption. In an in vitro HAT assay, As2O3 directly inhibited hMOF activity. hMOF over-expression not only increased resistance to As and caused less toxicity, but also effectively reversed reduced H4K16ac caused by As exposure. These data suggest a theoretical basis for elucidating the mechanism of As toxicity.
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