Tumor antigen PRAME is a potential therapeutic target of p53 activation in melanoma cells.

Upregulation of PRAME (preferentially expressed antigen of melanoma) has been implicated in the progression of a variety of cancers, including melanoma. The tumor suppressor p53 is a transcriptional regulator that mediates cell cycle arrest and apoptosis in response to stress signals. Here, we report that PRAME is a novel repressive target of p53.

Additional Sex Combs-like Family Associated with Epigenetic Regulation.

The additional sex combs-like (ASXL) family, a mammalian homolog of the () of , has been implicated in transcriptional regulation via chromatin modifications. Abnormal expression of ASXL family genes leads to myelodysplastic syndromes and various types of leukemia. De novo mutation of these genes also causes developmental disorders.

Biological and mechanical influence of three-dimensional microenvironment formed in microwell on multicellular spheroids composed of heterogeneous hair follicle stem cells.

Hair loss caused by malfunction of the hair follicle stem cells (HFSCs) and physical damage to the skin is difficult to recover from naturally. To overcome these obstacles to hair follicle (HF) regeneration, it is essential to understand the three-dimensional (3D) microenvironment and interactions of various cells within the HFs. Therefore, 3D cell culture technology has been used in HF regeneration research; specifically, multicellular spheroids have been generally adapted to mimic the 3D volumetric structure of the HF.

SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence.

SIRT1, a member of the mammalian sirtuin family, is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase with key roles in aging-related diseases and cellular senescence. However, the mechanism by which SIRT1 protein homeostasis is controlled under senescent conditions remains elusive. Here, we revealed that SIRT1 protein is significantly downregulated due to ubiquitin-mediated proteasomal degradation during stress-induced premature senescence (SIPS) and that SIRT1 physically associates with anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase.

Shikonin Binds and Represses PPARγ Activity by Releasing Coactivators and Modulating Histone Methylation Codes.

Shikonin, a natural ingredient produced by , has anti-inflammatory, anti-cancer, and anti-obesity effects. It also inhibits adipocyte differentiation; however, the underlying molecular and epigenetic mechanisms remain unclear. We performed RNA-sequencing of shikonin-treated 3T3-L1 cells.

BET Inhibitors Induce p53-Independent Growth Arrest in HCT116 Cells via Epigenetic Control of the E2F1/c-MYC Axis.

Although bromodomain and extraterminal (BET) inhibitors (BETis) have anti-tumor potential, the underlying molecular mechanism is poorly understood. We found that BETis effectively repressed cell growth via G1/S arrest and migration of HCT116 cells in a p53-independent manner. BETis increased the expression of p21WAF1 and repressed the expression of E2F target genes.

Kaempferol antagonizes adipogenesis by repressing histone H3K4 methylation at PPARγ target genes.

We previously demonstrated that kaempferol, a flavonoid present in various herbs, inhibits adipogenesis by repressing peroxisome proliferator-activated receptor γ (PPARγ) activity. Here, we focused on elucidation of the underlying mechanism using genome-wide tools. First, RNA sequencing (RNA-seq) analysis showed downregulation of genes involved in adipogenesis in response to kaempferol.

Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system.

The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system.

BAP1 shapes the bone marrow niche for lymphopoiesis by fine-tuning epigenetic profiles in endosteal mesenchymal stromal cells.

Hematopoiesis occurs within a unique bone marrow (BM) microenvironment, which consists of various niche cells, cytokines, growth factors, and extracellular matrix components. These multiple components directly or indirectly regulate the maintenance and differentiation of hematopoietic stem cells (HSCs). Here we report that BAP1 in BM mesenchymal stromal cells (MSCs) is critical for the maintenance of HSCs and B lymphopoiesis.

Deep Learning for Human Disease Detection, Subtype Classification, and Treatment Response Prediction Using Epigenomic Data.

Deep learning (DL) is a distinct class of machine learning that has achieved first-class performance in many fields of study. For epigenomics, the application of DL to assist physicians and scientists in human disease-relevant prediction tasks has been relatively unexplored until very recently. In this article, we critically review published studies that employed DL models to predict disease detection, subtype classification, and treatment responses, using epigenomic data.

Piperine inhibits adipocyte differentiation via dynamic regulation of histone modifications.

Previously, we reported that piperine, one of the major pungent components in black pepper, attenuates adipogenesis by repressing PPARγ activity in 3T3-L1 preadipocytes. However, the epigenetic mechanisms underlying this activity remain unexplored. Here, gene set enrichment analysis using microarray data indicated that there was significant downregulation of adipogenesis-associated and PPARγ target genes and upregulation of genes bound with H3K27me3 in response to piperine.

Asxl1 ablation in mouse embryonic stem cells impairs neural differentiation without affecting self-renewal.

Additional sex comb-like1 (Asxl1) is known as a chromatin modulator that plays dual functions in transcriptional regulation depending on the cell type. Recent studies using Asxl1 knockout mice revealed that Asxl1 is important for the proliferation and differentiation of hematopoietic progenitor cells, and the development of organs. Although we previously reported Asxl1 as a Sox2 target gene, its function in embryonic stem cells (ESCs) remains largely unknown.

Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis.

Although additional sex combs-like 1 (ASXL1) has been extensively described in hematologic malignancies, little is known about the molecular role of ASXL1 in organ development. Here, we show that Asxl1 ablation in mice results in postnatal lethality due to cyanosis, a respiratory failure. This lung defect is likely caused by higher proliferative potential and reduced expression of surfactant proteins, leading to reduced air space and defective lung maturation.

CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis.

Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite great progress in elucidating the transcriptional network of PPARγ, epigenetic regulation of this pathway by histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly bound to PPARγ through the co-repressor nuclear receptor (CoRNR) box 2 and repressed the transcriptional activity and adipogenic potential of PPARγ.

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood.

Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT).

Asxl1 deficiency in embryonic fibroblasts leads to cellular senescence via impairment of the AKT-E2F pathway and Ezh2 inactivation.

Although ASXL1 mutations are frequently found in human diseases, including myeloid leukemia, the cell proliferation-associated function of ASXL1 is largely unknown. Here, we explored the molecular mechanism underlying the growth defect found in Asxl1-deficient mouse embryonic fibroblasts (MEFs). We found that Asxl1, through amino acids 371 to 655, interacts with the kinase domain of AKT1.

Tumor antigen PRAME is up-regulated by MZF1 in cooperation with DNA hypomethylation in melanoma cells.

Elevated expression of preferentially expressed antigen in melanoma (PRAME) has been implicated in disease progression in a variety of cancers. However, the mechanisms underlying the transcriptional regulation of PRAME remain largely unexplored. Initially, we observed that PRAME was elevated in proportion to the malignant potential of melanoma cells.

CACUL1 functions as a negative regulator of androgen receptor in prostate cancer cells.

The androgen receptor (AR) plays a critical role in the initiation and progression of prostate cancer (PCa), and thus its regulation is an important tool in PCa therapy. Here, we report that CDK2-associated cullin 1 (CACUL1) directly associates with AR and suppresses AR transcriptional activity. In addition, CACUL1 represses histone demethylase LSD1-mediated AR transactivation by competing with LSD1 for AR binding.

CBX8 antagonizes the effect of Sirtinol on premature senescence through the AKT-RB-E2F1 pathway in K562 leukemia cells.

Although tyrosine kinase inhibitor (TKI) therapies are highly effective in the treatment of chronic myeloid leukemia (CML), frequent recurrence limits their usage and demands new approaches for CML therapy. Stress-induced premature senescence (SIPS) is considered a potential anticancer treatment, but the underlying mechanism remains elusive. Here, we report that Sirtinol, a known SIRT1 inhibitor, induces premature senescence and growth arrest in K562 CML cells.

The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1.

Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the retinoic acid derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels.

Role of Asxl1 in kidney podocyte development via its interaction with Wtip.

Additional sex comb-like (ASXL) family proteins are chromatin factors that function in transcriptional activation and repression. However, the underlying mechanisms and biological implications have not been well established. Here, we identified a LIM domain-containing protein, Wilms tumor 1-interacting protein (WTIP), as an ASXL1-binding partner.

Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway.

Mechanisms associated with the progression of non-alcoholic fatty liver disease (NAFLD) remain unclear. We attempted to identify the pattern of altered gene expression at different time points in a high fat diet (HFD)-induced NAFLD mouse model. The early up-regulated genes are mainly involved in the innate immune responses, while the late up-regulated genes represent the inflammation processes.

Repression of LXRα by a novel member of additional sex comb-like family, ASXL3.

Among the members of the additional sex comb-like (ASXL) family, ASXL3 remains unexplored. Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression.