Research progress on food-derived antioxidants for alleviating toxicity of endocrine disrupting chemicals / 环境与职业医学

Endocrine disrupting chemicals (EDCs) are a class of chemical substances widely present in daily-life environment, and can enter human body through various pathways, posing a threat to reproductive development and health. Oxidative stress (OS) is one of the most important fundamental mechanisms underlying the reproductive toxicity of EDCs. Numerous studies have found that exposure to EDCs can increase the levels of reactive oxygen species (ROS) in human reproductive system and reduce the activity and quantity of multiple enzymatic antioxidants, leading to oxidative stress and inducing damage to the reproductive system at various levels such as DNA and cells. Many research results have shown that supplementing food-derived non-enzymatic antioxidants can reduce ROS levels and increase the activity of enzymatic antioxidants, thereby reduce OS levels, and further repair EDCs-induced reproductive damage. In addition, many food-derived antioxidants are important elements involved in reproductive physiological activities and have protective effects on reproductive health. This paper summarized the reproductive toxicity of EDCs, including damage to reproductive cells, interference with hormone action, and influence on reproductive-related epigenetic regulation, elaborated the relationship between OS and reproductive toxicity of EDCs, and further summarized the alleviating effects and related mechanisms of food-derived antioxidants such as vitamins, trace elements, and plant polyphenols and pigments against reproductive toxicity of EDCs, aiming to provide a theoretical and scientific basis for prevention and treatment against reproductive toxicity of EDCs.

Advances in epigenetic regulation of Chinese hamster ovary cells / 生物工程学报

Chinese hamster ovary (CHO) cells play an irreplaceable role in biopharmaceuticals because the cells can be adapted to grow in suspension cultures and are capable of producing high quality biologics exhibiting human-like post-translational modifications. However, gene expression regulation such as transgene silencing and epigenetic modifications may reduce the recombinant protein production due to the decrease of expression stability of CHO cells. This paper summarized the role of epigenetic modifications in CHO cells, including DNA methylation, histone modification and miRNA, as well as their effects on gene expression regulation.

Advances on the correlation between hypoxia inducible factor and epigenetic modification / 国际儿科学杂志

Hypoxia inducible factor(HIF)is a key factor in the regulation of oxygen homeostasis, and its expression level is mainly influenced by oxygen concentration in the adaptation of the body to chronic hypoxia, with which many pediatric diseases are closely associated.The response to hypoxia can be altered by HIF and its mediated downstream signaling pathways, in addition to epigenetic modifications such as regulation of overall methylation or histone modification levels to adapt to hypoxic environments.Previous studies have shown that the transcriptional activity and stability of HIF are interrelated with various histone modifications including methylation/demethylation, hydroxylation, deacetylation, phosphorylation, and lactylation, which makes the study of epigenetic modification correlation deserves to be explored in depth as an important potential target for regulating HIF expression levels.

Chromatin Remodeling Factor SMARCA5 is Essential for Hippocampal Memory Maintenance via Metabolic Pathways in Mice / 神经科学通报·英文版

Gene transcription and new protein synthesis regulated by epigenetics play integral roles in the formation of new memories. However, as an important part of epigenetics, the function of chromatin remodeling in learning and memory has been less studied. Here, we showed that SMARCA5 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 5), a critical chromatin remodeler, was responsible for hippocampus-dependent memory maintenance and neurogenesis. Using proteomics analysis, we found protein expression changes in the hippocampal dentate gyrus (DG) after the knockdown of SMARCA5 during contextual fear conditioning (CFC) memory maintenance in mice. Moreover, SMARCA5 was revealed to participate in CFC memory maintenance via modulating the proteins of metabolic pathways such as nucleoside diphosphate kinase-3 (NME3) and aminoacylase 1 (ACY1). This work is the first to describe the role of SMARCA5 in memory maintenance and to demonstrate the involvement of metabolic pathways regulated by SMARCA5 in learning and memory.

CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain / 神经科学通报·英文版

Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms. The circRNAs are mainly enriched in the central nervous system. However, their function in various physiological and pathological conditions have yet to be determined. Here, we identified circFhit, an exon-intron circRNA expressed in GABAergic neurons, which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain. Moreover, we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R+ neurons by promoting the expression of its parental gene Fhit in cis. Mechanistically, circFhit was directly bound to the intronic region of Fhit, and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron. In summary, we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R+ neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

Research progress in influences of epigenetic modifications on PD-L1 expression in tumors / 国际肿瘤学杂志

Tumor cells expression of programmed death ligand-1 (PD-L1) is a major mechanism of immune escape and a predictor of therapeutic efficacy of immune checkpoint inhibitors. The expression of PD-L1 is regulated by a variety of mechanisms, among which epigenetic modifications such as DNA methylation, histone modification and non-coding RNA can promote the occurrence, development and drug resistance of tumors by regulating the expression of PD-L1. To clarify its regulation mechanism can bring new ideas for clinical immunotherapy of tumors.

Epigenetic regulation and retinal degenerative diseases / 中华实验眼科杂志

Epigenetics pertains to heritable alterations in gene expression when the nucleotide sequence remains unchanged.Epigenetic regulation mechanisms are diverse, among which DNA methylation, histone modification and non-coding RNA (ncRNA) regulation have been studied in depth.Epigenetic regulation is associated with a variety of human diseases.In the occurrence and development of retinal degenerative diseases, many epigenetic regulation processes such as DNA methylation, histone acetylation and ncRNA regulation have changed.DNA methylation is one of the important regulation processes in retinal degeneration.Aberrant DNA methylation patterns are associated with retinitis pigmentosa (RP), age-related macular degeneration (AMD), inflammation and oxidative stress.Histone acetylation is associated with RP, diabetic retinopathy (DR), glaucoma and retinal nerve ischemic injury.NcRNA is associated with RP, AMD, pathological angiogenesis, and DR.In this article, the application of epigenetic regulation in retinal degeneration was reviewed.

Targeting GATA1 and p2x7r Locus Binding in Spinal Astrocytes Suppresses Chronic Visceral Pain by Promoting DNA Demethylation / 神经科学通报·英文版

Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal diseases. In this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1 (GATA1) in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation (NCI). The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay, chromatin immunoprecipitation, patch clamp, and interference in vitro and in vivo. In addition, a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG island. We showed that NCI caused the induction of GATA1, Ten-eleven translocation 3 (TET3), and purinergic receptors (P2X7Rs) in astrocytes of the spinal dorsal horn, and demonstrated that inhibiting these molecules markedly increased the pain threshold, inhibited the activation of astrocytes, and decreased the spinal sEPSC frequency. NCI also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1-TET3 physical interaction and GATA1 binding at the p2x7r promoter. Importantly, we showed that demethylation of the p2x7r locus (and the attendant increase in P2X7R expression) was reversed upon knockdown of GATA1 or TET3 expression, and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r promoter. These results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r transcription in spinal dorsal horn astrocytes, and provide a potential therapeutic strategy by targeting GATA1 and p2x7r locus binding.

Mechanisms of alternative splicing in regulating plant flowering: a review / 生物工程学报

Flowering is a critical transitional stage during plant growth and development, and is closely related to seed production and crop yield. The flowering transition is regulated by complex genetic networks, whereas many flowering-related genes generate multiple transcripts through alternative splicing to regulate flowering time. This paper summarizes the molecular mechanisms of alternative splicing in regulating plant flowering from several perspectives, future research directions are also envisioned.

Piperlongumine Downregulates TERT Expression via STAT3 Pathway by Epigenetic Regulation in Gastric Cancer Cells / 胃肠病学

Background: Piperlongumine (PL) is an alkaloid compound extracted from piperlongum. Many studies have shown that PL has anti-tumor effects on a variety of tumor cells in vivo and in vitro. However, the specific mechanism needs to be further explored. Aims: To investigate the regulatory mechanism of PL on the expression of TERT in gastric cancer cells. Methods: Gastric cancer cells were treated with different doses of PL, AG490, respectively. CCK-8 and plate colony formation experiment were used to detect cell viability. Real-time fluorescent quantitative PCR was used to detect the expression of TERT mRNA. Western blotting was used to detect the protein expressions of TERT, STAT3, p-STAT3 and DNMT1. TRAP-ELISA was used to determine the telomerase activity. Luciferase reporter gene was used to detect the TERT promoter activity. Results: Compared with control group, gastric cancer cells viability in PL group was significantly decreased, colony formation ability was significantly reduced, TERT mRNA and protein expressions, as well as telomerase activity were significantly reduced, p-STAT3 and DNMT1 protein expressions were significantly downregulated. AG490 significantly inhibited gastric cancer cells viability, protein expressions of p-STAT3, DNMT1 and TERT. Conclusions: PL may inhibit gastric cancer cells viability through regulation of TERT expression via STAT3-mediated epigenetic regulation and it may become a new target drug for the treatment of gastric cancer in future.

Decreased miR-325-5p Contributes to Visceral Hypersensitivity Through Post-transcriptional Upregulation of CCL2 in Rat Dorsal Root Ganglia / 神经科学通报·英文版

Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chronic pain conditions. However, the role of miRNA-325-5p in chronic visceral pain remains unknown. The present study was designed to determine the roles and mechanism of miRNA-325-5p in a rat model of chronic visceral pain. This model was induced by neonatal colonic inflammation (NCI). In adulthood, NCI led to a significant reduction in the expression of miRNA-325-5p in colon-related dorsal root ganglia (DRGs), starting to decrease at the age of 4 weeks and being maintained to 8 weeks. Intrathecal administration of miRNA-325-5p agomir significantly enhanced the colorectal distention (CRD) threshold in a time-dependent manner. NCI also markedly increased the expression of CCL2 (C-C motif chemokine ligand 2) in colon-related DRGs at the mRNA and protein levels relative to age-matched control rats. The expression of CXCL12, IL33, SFRS7, and LGI1 was not significantly altered in NCI rats. CCL2 was co-expressed in NeuN-positive DRG neurons but not in glutamine synthetase-positive glial cells. Furthermore, CCL2 was mainly expressed in isolectin B4-binding- and calcitonin gene-related peptide-positive DRG neurons but in few NF-200-positive cells. More importantly, CCL2 was expressed in miR-325-5p-positive DRG neurons. Intrathecal injection of miRNA-325-5p agomir remarkably reduced the upregulation of CCL2 in NCI rats. Administration of Bindarit, an inhibitor of CCL2, markedly raised the CRD threshold in NCI rats in a dose- and time-dependent manner. These data suggest that NCI suppresses miRNA-325-5p expression and enhances CCL2 expression, thus contributing to visceral hypersensitivity in adult rats.

Direct interaction of DNMT inhibitors to PrP suppresses pathogenic process of prion

The conversion of the normal cellular prion protein (PrP) to the misfolded pathogenic scrapie prion protein (PrP) is the biochemical hallmark of prion replication. So far, various chemical compounds that inhibit this conformational conversion have been identified. Here, we report the novel anti-prion activity of SGI-1027 and its meta/meta analogue (M/M), previously known only as potent inhibitors of DNA methyltransferases (DNMTs). These compounds effectively decreased the level of PrP in cultured cells with permanent prion infection, without affecting PrP at the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a PrP aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded PrP aggregates, implying that binding of these compounds hinders the PrP conversion process. A series of binding and docking analyses demonstrated that both SGI-1027 and M/M directly interacted with the C-terminal globular domain of PrP, but only SGI-1027 bound to a specific region of PrP with high affinity, which correlates with its potent anti-prion efficacy. Therefore, we report SGI-1027 and related compounds as a novel class of potential anti-prion agents that preferentially function through direct interaction with PrP.

Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2

Renal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3'-UTR. Meanwhile, 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP), fluorogenic substrate ,-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP), and oxaliplatin uptake by OCT2 both and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.

Effects of EZH2 inhibitor DZNeP on osteogenic differentiation of periodontal ligament stem cells / 国际生物医学工程杂志

Objective To observe the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and to investigate the epigenetic regulation of EZH2 inhibitor DZNeP on osteogenic differentiation of hPDLSCs. Methods The hPDLSCs were isolated and cultured, and their proliferation under different concentrations of DZNeP (0, 1, 2, 5 and 10 μmol/L) was detected by MTT. The effects of DZNeP on osteogenic differentiation of hPDLSCs were observed by alkaline phosphatase (ALP) staining and alizarin red staining. The effect of DZNeP on the trimethylation of histone H3K27 in hPDLSCs was detected by immunofluorescence staining. Results Compared with the control group, the proliferation of hPDLSCs after 1, 2, 5 and 10 μmol/L DZNeP treatment for 48 h was significantly decreased, respectively (all P<0.05), and it was concentration-dependent. The result of ALP staining and alizarin red staining showed that DZNeP could promote the expression of early osteogenic markers ALP and the formation of advanced calcified nodules of hPDLSCs. The immunofluorescence staining result showed that the trimethylation fluorescence intensity of histone H3K27 was significantly decreased in the DZNeP group compared with the control group. Conclusions As an EZH2 inhibitor, DZNeP can inhibit the proliferation of hPDLSCs and promote the differentiation of hPDLSCs into osteoblasts in vitro, suggesting that DZNeP can be used as a potential small molecule drug for the treatment of periodontitis.

Tet2 regulates the function of mesenchymal stem cells / 生物工程学报

Tet2 (member 2 of the Tet family) plays an important role in DNA demethylation modification, epigenetic regulation, and hematopoiesis. In our previous study, we found that Tet2 knockout mice progressively developed lymphocytic leukemia and myeloid leukemia with aging. However，the role of Tet2 in bone marrow microenvironment is unclear. Here in this study, we found that more Tet2-/- mesenchymal stem cells (MSCs) from bone marrow were in the G2/M cell cycle stages. The division time of Tet2-/- MSCs was shorter than that of the control cells. The growth rate of Tet2-/- MSCs was accelerated. The cobblestone area-forming cells assay (CAFC) showed that Tet2 knockout MSCs supported the expansion of hematopoietic stem cells (HSCs) and the differentiation of HSCs was skewed towards myeloid cells. Through the dot blotting experiment, we found that the total methylation level was increased in Tet2-/- bone marrow cells (BM). We used the methylation-chip to analyze the methylation level of Tet2-/- bone marrow cells and found that the level of methylation was increased in the transcriptional starting area (TSS), exons (EXONS) and 3' untranslated region (3' UTR). Moreover, we found that the cytokines secreted by Tet2-/- MSCs, such as IL-8 and IL-18, were decreased. While the expressions of GM-CSF and CCL-3, which supported hematopoietic stem cells to differentiate to myeloid cells, were increased in Tet2-/- MSCs. Our results demonstrated that Tet2 regulates MSCs to support hematopoiesis.

Deep in shadows: Epigenetic and epigenomic regulations of medicinal plants / 中草药·英文版

Around 60% of the extant plants have medicinal and health-promoting values. Genuine medicinal material (geoherb) is produced in particular geographic regions, that is defined ecological environment and cultivation pipeline. The clinical efficacy of a geoherb is superior to that of the same medicinal plant growing in other regions. The special medicinal features of a plant are determined by its genome, while the proper ecological conditions have major effects on the formation of a geoherb, which is at least partially mediated by the epigenetics. By epigenetics/epigenomics, researchers uncover the complexities of the influence of the environment on the expression of genes that control medicinal plant growth, development, stress responses, and medicinal phytometabolite yield, and put the other “omics layers” in a meaningful biological context. The unique phenotypes of geoherb are closely related to the growth, development, and stress responses of medicinal plants. In addition to the commonly known genetic control, epigenetic machineries, active at the population level, play an essential role in the formation of geoherbs. This contribution gives a comprehensive overview of the epigenetic regulation of medicinal plants, and the associated microbes, and the role of DNA methylation, small non-coding RNA, transposable elements, and histone modifications in the gene expression regulation of geoherbs and relevant microbiota. The epigenetic and epigenomic mechanisms should be highlighted in the study of specific phenotype and indigenousness of geoherbalism. Revealing the correlation between epigenetics and geoherbs could shed light on the quality assessment, authentication, molecular breeding, and sustainable utilization of medicinal plants and the associated microbes.

The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation

A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors (HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through HIF-1α and HIF-2α. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.

Mutations of ASXL1 gene in myelodysplastic syndromes / 白血病·淋巴瘤

Objective To investigate the mutations of epigenetic regulation factor ASXL1 gene in myelodysplastic syndrome(MDS).Methods Mutation analysis of ASXL1 gene in 53 de novo MDS patients and 20 healthy persons was performed by using polymerase chain reaction(PCR)followed by sequence analysis at DNA level.The clinical and laboratory characteristics were compared in MDS patients with ASXL1 gene mutation and ASXL1 wild type.ASXL1 mutation in mRNA level was detected by using reverse transcription PCR(RT-PCR)followed by sequence analysis.Results ASXL1 gene mutations were observed in 9 cases(16.9%)of 53 MDS patients.6 mutation types were detected,including 4 frameshift mutations types(2 cases with p.Glu635ArgfsX15,3 cases with p.Gly646TrpfsX12,1 case with p.Ala640GlyfsX14 and 1 case with p.Gly790TrpfsX10)and 2 nonsense mutation types(1 case with p.Gln1063X and 1 case with p.Gln695X).All the mutations were heterozygous,and p.Gly790TrpfsX10 and p.Gln695X were new mutation types.In addition,a single nucletide polymorphism(SNP)p.Gly652Ser was also detected in 4 cases with MDS.5 cases of p.G652S SNP and 1 case of p.Leu1173Leu SNP were detected in 20 healthy people.Frameshift mutation(p.Gly646TrpfsX12)could be detected at mRNA level by using RT-PCR.Differences were not observed in red blood cell counts,white blood cell counts,platelet counts,hemoglobin levels,reticulocyte,neutrophil granulocyte,the peripheral blood lymphocytes percentage,T-cell subsets in the peripheral blood,the proportion of primitive cell in the marrow and MDS types between the patients with ASXL1 gene mutation and ASXL1 wild type patients(P >0.05).Conclusion There is a high frequency of ASXL1 gene mutation in MDS patients,which can be detected at mRNA level.

Mutations of ASXL1 gene in myelodysplastic syndromes / 白血病·淋巴瘤

Objective To investigate the mutations of epigenetic regulation factor ASXL1 gene in myelodysplastic syndrome(MDS).Methods Mutation analysis of ASXL1 gene in 53 de novo MDS patients and 20 healthy persons was performed by using polymerase chain reaction(PCR)followed by sequence analysis at DNA level.The clinical and laboratory characteristics were compared in MDS patients with ASXL1 gene mutation and ASXL1 wild type.ASXL1 mutation in mRNA level was detected by using reverse transcription PCR(RT-PCR)followed by sequence analysis.Results ASXL1 gene mutations were observed in 9 cases(16.9%)of 53 MDS patients.6 mutation types were detected,including 4 frameshift mutations types(2 cases with p.Glu635ArgfsX15,3 cases with p.Gly646TrpfsX12,1 case with p.Ala640GlyfsX14 and 1 case with p.Gly790TrpfsX10)and 2 nonsense mutation types(1 case with p.Gln1063X and 1 case with p.Gln695X).All the mutations were heterozygous,and p.Gly790TrpfsX10 and p.Gln695X were new mutation types.In addition,a single nucletide polymorphism(SNP)p.Gly652Ser was also detected in 4 cases with MDS.5 cases of p.G652S SNP and 1 case of p.Leu1173Leu SNP were detected in 20 healthy people.Frameshift mutation(p.Gly646TrpfsX12)could be detected at mRNA level by using RT-PCR.Differences were not observed in red blood cell counts,white blood cell counts,platelet counts,hemoglobin levels,reticulocyte,neutrophil granulocyte,the peripheral blood lymphocytes percentage,T-cell subsets in the peripheral blood,the proportion of primitive cell in the marrow and MDS types between the patients with ASXL1 gene mutation and ASXL1 wild type patients(P >0.05).Conclusion There is a high frequency of ASXL1 gene mutation in MDS patients,which can be detected at mRNA level.

Targeting Strategies for Breast Cancer Stem Cells:Current Status / 中山大学学报(医学科学版)

The breast cancer stem cell theory provides a theoretical basis for explaining phenotypic and functional heterogeneity of breast cancer. These breast cancer stem cells(CSCs)promote tumor growth and are closely related to breast cancer intrinsic drug resistance. Therefore,targeted therapy of breast CSCs has become a hot area in basic and clinical research. There is growing evidence that nanoparticles can kill cancer by targeting breast CSCs ,such as targeted tumor stem cell-specific expressed surface markers(AL-DH1,CD44,and CD90),tumor stem cell stemness-related NOTCH,Hedgehog and TGF-βsignaling pathways. In this review,we summarized the characteristics and research status of breast CSCs ,and the application of nanotechnology in the treatment of breast cancer.In addition,we also summarized the research status of epigenetic drugs aimed to restrain the reprogramming of breast cancer cells.