Abstract:
:Osteoclasts are absorptive cells that play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role of epigenetic regulation in osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation (H3K79me), during osteoclast formation. Using RANKL-induced RAW264.7 macrophage cells as an osteoclast differentiation model, we found that DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. In addition, DOT1L inhibition increased osteoclast surface area and accelerated bone-mass reduction in a mouse ovariectomy (OVX) model of osteoporosis without alter osteoblast differentiation. DOT1L inhibition increase reactive oxygen species (ROS) generation and autophagy activity, and cell migration in pre-osteoclasts. Moreover, it strengthened expression of osteoclast fusion and resorption-related protein CD9 and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-regulated, H3K79me2-mediated, epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Gao Y,Ge Wdoi
10.1038/s41419-017-0040-5subject
Has Abstractpub_date
2018-01-18 00:00:00pages
33issue
2issn
2041-4889pii
10.1038/s41419-017-0040-5journal_volume
9pub_type
杂志文章abstract::Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticu...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2159-z
更新日期:2019-12-04 00:00:00
abstract::Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induc...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2010.67
更新日期:2010-10-21 00:00:00
abstract::The Nogo receptor and paired immunoglobulin-like receptor B (PIR-B) are receptors for three myelin-derived axon-growth inhibitors, including myelin-associated glycoprotein (MAG). In this study, we report that the p75 receptor is required for the signal transduction of PIR-B, which interacted with p75 upon ligand bindi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2011.85
更新日期:2011-09-01 00:00:00
abstract::Sepsis is a systemic inflammation caused by infection. The balance between M1-M2 macrophage polarization has an essential role in the pathogenesis of sepsis. However, the exact mechanism underlying macrophage polarization is unclear. We previously showed that levels of malignant fibrous histiocytoma amplified sequence...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.102
更新日期:2017-05-04 00:00:00
abstract::Many cancer therapies are being developed for the induction of durable anti-tumor immunity, especially for malignant tumors. The activation of antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), can bridge innate and adaptive immune responses against tumors. However, APCs have an immunosu...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1459-7
更新日期:2019-03-04 00:00:00
abstract::Evidence is mounting that proinflammatory and proapoptotic thioredoxin-interacting protein (TXNIP) has a causative role in the development of diabetes. However, there are no studies investigating the role of TXNIP in diabetic retinopathy (DR). Here, we show that, in diabetic rats, TXNIP expression and hexosamine biosy...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2010.42
更新日期:2010-08-19 00:00:00
abstract::miR-148a-3p downregulation has emerged as a critical factor in cancer progression yet, the underlying mechanisms of miR-148a-3p expression pattern and its function in bladder cancer remains to be elucidated. Here, we illustrate that miR-148a-3p is frequently downregulated in bladder cancer and that its expression may ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.373
更新日期:2016-12-01 00:00:00
abstract::Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repress...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2010.10
更新日期:2010-04-01 00:00:00
abstract::Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuronal loss that initiates in the substantia nigra pars compacta and by the formation of intracellular inclusions mainly constituted by aberrant α-synuclein (α-syn) deposits known as Lewy bodies. Most cases ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2092-1
更新日期:2019-11-12 00:00:00
abstract::Acute promyelocytic leukemia (APL) therapy involves the compounds cytotoxic to both malignant tumor and normal cells. Relapsed APL is resistant to subsequent chemotherapy. Novel agents are in need to kill APL cells selectively with minimal toxicity. DDX5 has been recognized to be a novel target to suppress acute myelo...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-02759-5
更新日期:2020-07-20 00:00:00
abstract::SAM and SH3 domain-containing 1 (SASH1), a scaffold protein, is regarded as a tumor suppressor. Recent studies have verified the decreased expression of SASH1 in many tumors. Our previous clinical investigation found that SASH1 was widely expressed in normal brain tissues but reduced or absent in glioma tissues. Howev...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1645-7
更新日期:2019-05-28 00:00:00
abstract::Tumor-associated macrophages (TAMs) represent potential targets for anticancer treatments as these cells play critical roles in tumor progression and frequently antagonize the response to treatments. TAMs are usually associated to an M2-like phenotype, characterized by anti-inflammatory and protumoral properties. This...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0757-9
更新日期:2018-06-27 00:00:00
abstract::The original version of this Article contained an error in Fig. 1, in which a number of incorrect fluorescence images were inadvertently incorporated into the panel. This has been corrected in both the PDF and HTML versions of the Article. ...
journal_title:Cell death & disease
pub_type: 已发布勘误
doi:10.1038/s41419-019-1422-7
更新日期:2019-03-12 00:00:00
abstract::Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Sinusoidal endothelial cells contribute to myofibroblast activation and liver fibrosis by undergoing endothelial-mesenchymal transition (EndMT). The...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2101-4
更新日期:2019-11-27 00:00:00
abstract::Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and suppresses gene expression by catalyzing histone H3 methylation on lysine 27. EZH2 is overexpressed in metastatic prostate cancer and has been shown to promote cell proliferation and metastasis. Here we show that EZH2 ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.454
更新日期:2014-10-23 00:00:00
abstract::Direct pharmacological targeting of the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is an attractive therapeutic strategy for treating cancer. Obatoclax is a pan-BCL-2 family inhibitor currently in clinical development. Here we show that, although obatoclax can induce mitochondrial apoptosis dependent on BCL-2 ass...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2010.86
更新日期:2010-12-16 00:00:00
abstract::The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.355
更新日期:2013-10-03 00:00:00
abstract::Paired-box 6 (PAX6) is an important transcription factor required for the function of human neuroectodermal epithelial tissues. Previous studies have suggested that it is also expressed in several types of tumors and has an oncogenic role. However, little is known about its role in non-small cell lung cancer (NSCLC). ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1591-4
更新日期:2019-04-25 00:00:00
abstract::It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. However, little is known of the mechanisms involved, particularly with respect to the organisation of CSCs as stem-progenitor-differentiated cell hierarchies. Here we aimed to elucidate the relationship between CS...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.379
更新日期:2017-10-19 00:00:00
abstract::Accumulating evidences indicate that microRNAs (miRNAs) play vital roles in multiple diseases, including cancer. In the present study, we showed that miR-6775-3p plays a tumor suppressive role in esophageal squamous cell carcinoma (ESCC). High expression miR-6775-3p is associated with good clinical outcomes of ESCC pa...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1119-3
更新日期:2018-10-17 00:00:00
abstract::Transient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia/reperfusion (I/R). Recently, we found that treatment with a selective TRPV4 antagonist HC-067047 significantly reduced infarct size, decreased troponin T levels and improved cardiac...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.227
更新日期:2017-05-25 00:00:00
abstract::The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress is a feature of many neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease (PD). Although the vast majority of PD is sporadic, mutations in a number of genes including PARK7 which encodes...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1354-2
更新日期:2019-02-12 00:00:00
abstract::Spermidine, a natural polyamine presented widely in mammalian cells, has been implicated to extend the lifespan of several model organisms by inducing autophagy. However, the effect of spermidine against neuronal damage has not yet been fully determined. In this study, neuronal cell injury was induced by treating PC12...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.161
更新日期:2017-04-06 00:00:00
abstract::We recently reported that microRNA (miR)-145 is downregulated and induces apoptosis in human bladder cancer cells. Also, it is suggested that the ectopic expression of miR-145 induces apoptosis with the induction of TRAIL expression in several cancer cells. Here, we demonstrated a novel mechanism of apoptosis inductio...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.11
更新日期:2013-02-07 00:00:00
abstract::Copious evidence demonstrates the crucial role of Rho GTPase-activating proteins in human malignancies. The downregulation of Rho GTPase-activating protein 15 (ARHGAP15), a Rac1-specific GAP, has been observed in glioma and pancreatic ductal adenocarcinoma. The present study explored the expression in colorectal cance...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0707-6
更新日期:2018-06-04 00:00:00
abstract::Numerous evidences have shown that circular RNAs (circRNAs) play a key role in regulating the pathogenesis of cancer. However, the mechanism of circRNAs in urothelial carcinoma of bladder (UCB) remains largely unclear. In this study, we found circFAM114A2 was significantly downregulated both in UCB tissue specimens an...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2226-5
更新日期:2020-01-22 00:00:00
abstract::We reported previously that adult (HRAS-/-; NRAS-/-) double knockout (DKO) mice showed no obvious external phenotype although lower-than-expected numbers of weaned DKO animals were consistently tallied after crossing NRAS-KO and HRAS-KO mice kept on mixed genetic backgrounds. Using mouse strains kept on pure C57Bl/6 b...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2075-2
更新日期:2019-11-04 00:00:00
abstract::The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' com...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.156
更新日期:2014-04-24 00:00:00
abstract::Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03054-z
更新日期:2020-10-14 00:00:00
abstract::Dalbergia odorifera has been traditionally used as a medicine to treat many diseases. However, the role of 2,4,5-trimethoxyldalbergiquinol (TMDQ) isolated and extracted from D. odorifera in osteoblast function and the underlying molecular mechanisms remain poorly understood. The aim of this study was to investigate th...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.185
更新日期:2015-07-16 00:00:00