bioRxiv Science⌕ Search

Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 991 records · Page 55Linked to original sources
bioRxiv2019

Sex differences in electrophysiological properties of mouse mPOA neurons revealed by in vitro whole-cell recordings

The medial preoptic area (mPOA) of the hypothalamus is sexually dimorphic and controls sexually dimorphic display of male mating and parental care. Yet, despite extensive characterization of sex differences in the mPOA, we know surprisingly little about whether or how male and female mPOA neurons differ electrophysiologically, which relate more directly to neuronal firing and behavioral pattern generation. In this study, we performed whole-cell patch clamp recordings of the mPOA in acute brain slices cut from virgin adult mice, and compared in total 29 electrophysiological parameters between male and female mPOA neurons. We find that resting membrane potential (Vm), input resistance (Rm), time constant ({tau}m), threshold (Vth) and minimum current (rheobase) required to generate an action potential differ significantly between male and female in a cell-type dependent manner. Nonetheless, there is little evidence for profuse sex differences in neuronal excitability, except for a higher probability of rebound neurons in males. Depletion of male gonadal hormones in adulthood partially de-masculinizes sexually dimorphic electrophysiological parameters, suggesting that some of these sex differences may establish during development. Furthermore, as a demonstration of the behavioral relevance of these sex differences, we show that pharmacologic blockage of currents mediated by T-type Ca2+ channel, which underlie rebound and tends to be larger in male mPOA neurons, result in behavioral deficits in male mating. In summary, we have identified key sex differences in electrophysiological properties of mPOA neurons that likely contribute to sexually dimorphic display of behaviors.\n\nSignificance StatementSex represents an important biological variable that impact an individuals behaviors, physiology and disease susceptibility. Indeed, sex differences in the nervous system manifest across many different levels and scales. Yet, throughout previous multifaceted investigations on sex differences in the brain, electrophysiological characterizations, which could potentially bridge cellular and molecular sex differences with sexually dimorphic brain functions and behaviors, remains scant. Here, focusing on an evolutionarily conserved sexually dimorphic nucleus, we investigated sex differences in electrophysiological properties of mPOA neurons and its modulation by gonadal hormones in adult males via in vitro whole-cell patch clamp. As a result, we identified novel sex differences in electrophysiological properties that likely contribute to sexually dimorphic display of behaviors and physiological functions.

neuroscience↗
bioRxiv2019

Genomic profiling of circulating tumor DNA reveals genetics and residual disease in NK/T lymphoma

BackgroundExtranodal NK/T-cell lymphoma, nasal type (ENTKL), is an aggressive hematological malignancy with poor prognosis. Early detection of tumors at initial diagnosis or during routine surveillance is important for improving survival outcomes. Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool for monitoring disease status. Here, we investigated the feasible of ctDNA detection in ENTKL. MethodsPlasma ctDNA was assessment were based on blood specimens that were collected from 65 patients recently diagnosed with ENKTL at the hematology medical center of Xinqiao Hospital, longitudinal samples collected under chemotherapy also included. Gene mutation spectrum of ENKTL was analyzed via cancer personalized profiling sequencing (CAPP-Seq). This study is registered with ClinicalTrials.gov (ChiCTR1800014813) ResultsFrom February 2017 to September 2019, 65 patients were enrolled, we found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%), NOTCH1 (7.7%). The mutation frequencies of KMT2D was significantly higher in stage III-IV, and mutations in KMT2D, ASXL3 and JAK3 were significantly correlated with the metabolic tumor burden of the patients. Compared with tumor tissue DNA, ctDNA profiling showed good concordance. Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequency of genes. Compared with PET/CT, ctDNA has more advantages for tracking residual disease in patients. In addition, we also found that mutated KMT2D predicted poor prognosis in patients. ConclusionCollectively, our results provide evidence that ctDNA may serve as a novel precision medicine biomarker in ENKTL.

genomics↗
bioRxiv2019

Molecular characterization of carbapenem-resistant Klebsiella pneumoniae isolates with focus on antimicrobial resistance

The enhancing incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP)-mediated infections in Mengchao Hepatobiliary Hospital of Fujian Medical University in 2017 is the motivation behind this investigation to study gene phenotypes and resistance-associated genes of emergence regarding the CRKP strains. In current study, seven inpatients are enrolled in the hospital with complete treatments. The carbapenem-resistant K. pneumoniae whole genome is sequenced using MiSeq short-read and Oxford Nanopore long-read sequencing technology. Prophages are identified to assess genetic diversity within CRKP genomes. The investigation encompassed eight CRKP strains that collected from the patients enrolled as well as the environment, which illustrate that blaKPC-2 is responsible for phenotypic resistance in six CRKP strains that K. pneumoniae sequence type (ST11) is informed. The plasmid with IncR, ColRNAI and pMLST type with IncF[F33:A-:B-] co-exist in all ST11 with KPC-2-producing CRKP strains. Along with carbapenemases, all K. pneumoniae strains harbor two or three extended spectrum {beta}-lactamase (ESBL)-producing genes. fosA gene is detected amongst all the CRKP strains. The single nucleotide polymorphisms (SNP) markers are indicated and validated among all CRKP strains, providing valuable clues for distinguishing carbapenem-resistant strains from conventional K. pneumoniae. In conclusion, ST11 is the main CRKP type, and blaKPC-2 is the dominant carbapenemase gene harbored by clinical CRKP isolates from current investigations.

bioengineering↗
bioRxiv2019

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

Alzheimers disease (AD) is extremely complex for both causal mechanism and clinical manifestation, requiring efforts to uncover its diversity and the corresponding mechanisms. Here, we applied a modelling analysis to investigate the regulation divergence among a large-scale cohort of AD patients. We found that transcription regulation tended to get degenerated in AD patients, which contributed to disease development and the detrimental clinical outcomes, mainly by disrupting protein degradation, neuroinflammation, mitochondrial and synaptic functions. To measure the accumulated effects, we came up with a new concept, regulation loss burden, which better correlated with AD related clinical manifestations and the ageing process. The epigenetic studies to multiple active regulation marks also supported a tendency of regulation loss in AD patients. Our finding can lead to a unified model as AD causal mechanism, where AD and its diversity are contributed by accumulated degeneration of transcriptional regulation.\n\nThe significance of this study is that: (1) it is the first system biology investigation to transcription regulation divergence among AD patients; (2) we observed an accumulated degeneration of transcription regulation, which well correlates with detrimental clinical outcomes; (3) transcriptional degeneration also contributes to the ageing process, where its correlation with ages is up to 0.78.

neuroscience↗
bioRxiv2019

Disruption of NOX2-dependent Oxidative Injury with a Targeted Gene-Therapy Approach Prevents Atrial Fibrillation in a Canine Model

Atrial fibrillation is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal as they are not targeted to the molecular mechanisms underlying AF. In this study, we demonstrated using a novel gene-based strategy in a clinically relevant large animal of AF that oxidative injury is a key mechanism underlying the onset and perpetuation of AF. First, we demonstrated that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through induction of NADPH oxidase 2 (NOX2) and generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electrical remodeling in AF by upregulating a constitutively active form of acetylcholine-dependent K+ current (IKACh) - called IKH - by a mechanism involving frequency-dependent activation of protein kinase C epsilon (PKC{varepsilon}). To understand the mechanism by which oxidative injury promotes the genesis and/or maintenance of AF, we performed targeted injection of NOX2 shRNA in atria of normal dogs followed by rapid atrial pacing. The time to onset of non-sustained AF increased by more than 5-fold in NOX2 shRNA treated dogs. Furthermore, animals treated with NOX2 shRNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, with attenuated activation of PKC{varepsilon}, a likely molecular mechanism underlying this beneficial electrophysiological remodeling. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.\n\nOne Sentence SummaryTargeted disruption of NOX2-dependent oxidative injury with a novel gene therapy approach prevents onset as well as perpetuation of atrial fibrillation.

physiology↗
bioRxiv2019

Expressed barcodes enable clonal characterization of chemotherapeutic responses in chronic lymphocytic leukemia

The remarkable evolutionary capacity of cancer is a major challenge to current therapeutic efforts. Fueling this evolution is its vast clonal heterogeneity and ability to adapt to diverse selective pressures. Although the genetic and transcriptional mechanisms underlying these responses have been independently evaluated, the ability to couple genetic alterations present within individual clones to their respective transcriptional or functional outputs has been lacking in the field. To this end, we developed a high-complexity expressed barcode library that integrates DNA barcoding with single-cell RNA sequencing through use of the CROP-seq sgRNA expression/capture system, and which is compatible with the COLBERT clonal isolation workflow for subsequent genomic and epigenomic characterization of specific clones of interest. We applied this approach to study chronic lymphocytic leukemia (CLL), a mature B cell malignancy notable for its genetic and transcriptomic heterogeneity and variable disease course. Here, we demonstrate the clonal composition and gene expression states of HG3, a CLL cell line harboring the common alteration del(13q), in response to front-line cytotoxic therapy of fludarabine and mafosfamide (an analog of the clinically used cyclophosphamide). Analysis of clonal abundance and clonally-resolved single-cell RNA sequencing revealed that only a small fraction of clones consistently survived therapy. These rare highly drug tolerant clones comprise 94% of the post-treatment population and share a stable, pre-existing gene expression state characterized by upregulation of CXCR4 and WNT signaling and a number of DNA damage and cell survival genes. Taken together, these data demonstrate at unprecedented resolution the diverse clonal characteristics and therapeutic responses of a heterogeneous cancer cell population. Further, this approach provides a template for the high-resolution study of thousands of clones and the respective gene expression states underlying their response to therapy.

cancer biology↗
bioRxiv2019

An integrated Asian human SNV and indel benchmark combining multiple sequencing methods

Precision medicine of human requires an accurate and complete reference variant benchmark for different populations. A human standard cell line of NA12878 provides a good reference for part of the human populations, but it is still lack of a fine reference standard sample and variant benchmark for the Asians. Here, we constructed a stabilized cell line of a Chinese Han volunteer. We received about 4.16T clean data of the sample using eight sequencing strategies in different laboratories, including two BGI regular NGS platforms, three Illumina regular NGS platforms, two linked-read libraries, and PacBio CCS model. The sequencing depth and reference coverage of eight sequencing strategies have reached the saturation. We detected small variants of SNPs and Indels using the eight data sets and obtained eight variant sets by performing a series of strictly quality control. Finally, we got 3.35M SNPs and 349K indels supported by all of sequencing data, which could be considered as a high confidence standard small variant sets for the studies. Besides, we also detected 5,913 high quality SNPs located in the high homologous regions supported by both linked-reads and CCS data benefited by their long-range information, while these regions are recalcitrant to regular NGS data due to the limited mappability and read length. We compared the later SNPs against the public databases and 969 sites of them were novel SNPs, indicating these SNPs provide a vital complement for the variant database. Moreover, we also phased more than 99% heterozygous SNPs also supported by linked-reads and CCS data. This work provided an integrated Asians SNV and indel benchmark for the further basic studies and precision medicine.

genomics↗
bioRxiv2019

TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism

PI3K/AKT signaling is known to regulate cancer metabolism but whether metabolic pathway feedbacks and regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal cross-talks between the PI3K/AKT signal and PPP branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of PPP, by inhibiting a newly identified E3 ligase TIRM21, and promotes PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of an AKT inhibitor PHLDA3. Knockout TRIM21 or PHLDA3 promotes the cross-talks and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of these reciprocal cross-talks may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

cancer biology↗
bioRxiv2019

Modulating cellular cytotoxicity and phototoxicity of fluorescent organic salts through counterion pairing

Light-activated theranostics offer promising opportunities for disease diagnosis, image-guided surgery, and site-specific personalized therapy. However, current fluorescent dyes are limited by low brightness, high cytotoxicity, poor tissue penetration, and unwanted side effects. To overcome these limitations, we demonstrate a platform for optoelectronic tuning, which allows independent control of the optical properties from the electronic properties of fluorescent organic salts. This is achieved through cation-anion pairing of organic salts that can modulate the frontier molecular orbital without impacting the bandgap. Optoelectronic tuning enables decoupled control over the cytotoxicity and phototoxicity of fluorescent organic salts through selective generation of mitochondrial reactive oxygen species that control cell viability. We show that through counterion pairing, organic salt nanoparticles can be tuned to be either nontoxic for enhanced imaging, or phototoxic for improved photodynamic therapy.

bioengineering↗
bioRxiv2019

Cryo-EM structure of the human Mixed Lineage Leukemia-1 complex bound to the nucleosome

Mixed Lineage Leukemia (MLL) family histone methyltransferases are the key enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanism by which the MLL complexes recognize histone H3K4 within the nucleosome core particle (NCP) remains unclear. Here, we report the single-particle cryo-electron microscopy (cryo-EM) structure of the human MLL1 core complex bound to the NCP. The MLL1 core complex anchors on the NCP through RbBP5 and ASH2L, which interacts extensively with nucleosomal DNA as well as the surface close to histone H4 N-terminal tail. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, allowing symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

biochemistry↗
bioRxiv2019

The microstructure investigation of plant architecture with X-ray microscopy

BackgroundIn recent years, the plant morphology has been well studied by multiple approaches at cellular and subcellular levels. Two-dimensional (2D) microscopy techniques offer imaging of plant structures on a wide range of magnifications for researchers. However, subcellular imaging is still challenging in plant tissues like roots and seeds.\n\nResultsHere we use a three-dimensional (3D) imaging technology based on the ZEISS X-ray microscope (XRM) Versa and analyze several plant tissues from different plant species. The XRM provides new insights into plant structures using non-destructive imaging at high-resolution and high contrast. We also developed a workflow aiming to acquire accurate and high-quality images in the context of the whole specimen. Multiple plant samples including rice, tobacco, Arabidopsis and maize were used to display the differences of phenotypes, which indicates that the XRM is a powerful tool to investigate plant microstructure.\n\nConclusionsOur work provides a novel observation method to evaluate and quantify tissue specific differences for a range of plant species. This new tool is suitable for non-destructive seed observation and screening.

plant biology↗
bioRxiv2019

Maternal circulating syncytiotrophoblast-derived extracellular vesicles contain biologically active 5’-tRNA halves

The placenta releases syncytiotrophoblast-derived extracellular vesicles (STB-EV) into the maternal circulation throughout gestation. STB-EV dependent signalling is believed to contribute to the widespread maternal adaptive physiological changes seen in pregnancy. Transfer RNA (tRNA) halves have been identified in vesicles released from other human and murine organ systems, which alter gene expression in target cells. Here, we characterise tRNA-half expression in STB-EV and demonstrate biological activity of a highly abundant tRNA-half. Short RNA from ex-vivo, dual-lobe placental perfusion STB-EV was sequenced, showing that most (>95%) comprised tRNA species. Whole placental tissue contained <50% tRNA species, suggesting selective packaging and export of tRNA into STB-EV. Most tRNA within STB-EV were 5-tRNA halves cleaved at 30-32 nucleotides. The pattern of tRNA expression differed depending on the size/origin of the STB-EV; this was confirmed by qPCR. Protein synthesis was suppressed in human fibroblasts when they were cultured with a 5-tRNA half identified from STB-EV sequencing. This study is the first to evaluate tRNA species in STB-EV. The presence of biologically active 5-tRNA halves, specific to a vesicular origin, suggests a novel mechanism for maternal-fetal signalling in normal pregnancy.

physiology↗
bioRxiv2019

A unique lower X-gate in TASK channels traps inhibitors within the vestibule

TASK channels are unusual members of the two-pore domain potassium (K2P) channel family, with unique and unexplained physiological and pharmacological characteristics. TASKs are found in neurons1,2, cardiomyocytes3-5 and vascular smooth muscle cells6 where they are involved in regulation of heart rate7, pulmonary artery tone6,8, sleep/wake cycles9 and responses to volatile anaesthetics9-12. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli13,14. Unlike other K2P channels, TASK channels have the capacity to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. These characteristics make the TASK channels some of the the most easily druggable potassium channels, and indeed TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnea (OSA) and atrial fibrillation (Afib)15 (The DOCTOS and SANDMAN Trials). Generally, potassium channels have an intramembrane vestibule with a selectivity filter above and a gate with four parallel helices below. However, K2P channels studied to date all lack a lower gate. Here we present the structure of TASK-1, revealing a unique lower gate created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance, which we designate as an \"X-gate\". This structure is formed by six residues (V243LRFMT248) that are essential for responses to volatile anaesthetics11, neuro-transmitters16 and G-protein coupled receptors16. Interestingly, mutations within the X-gate and surrounding regions drastically affect both open probability and activation by anaesthetics. Structures of TASK-1 with two novel, high-affinity blockers, shows both inhibitors bound below the selectivity filter, trapped in the vestibule by the X-gate, thus explaining their exceptionally low wash-out rates. Thus, the presence of the X-gate in TASK channels explains many aspects of their unusual physiological and pharmacological behaviour, which is invaluable for future development and optimization of TASK modulators for treatment of heart, lung and sleep disorders.

molecular biology↗
bioRxiv2019

The methodological quality of animal studies: A cross-sectional study based on the SYRCLEs risk of bias tool

ObjectiveTo assess the methodological quality of animal studies published in China and abroad using the SYRCLEs risk of bias tool, and to provide references to improve the methodological quality of animal studies to encourage high quality preclinical studies.\n\nMethodsAn electronic search was performed in the Chinese Scientific Citation Database (CSCD) and Web of Science from 2014 to October 2018. Document screening and data extraction were performed independently by four researchers. The methodological quality of the included studies was assessed using the SYRCLEs risk of bias tool. Statistical analysis was performed using SPSS23.\n\nResultsA total of 2764 animal studies were included. Of the studies, 984 were published in English and 1780 were in Chinese. The citation frequency of more than 90% of the included studies was less than 5. The results of methodological quality assessment showed that 36.36% (8/22) of the sub-items were rated as \"low risk\" in more than 50% of the included studies, of which 75% (6/8) were rated as \"low risk\" in more than 80% of the included studies. A total of 59.09% (13/22) of the sub-items were rated as \"low risk\" in less than 30% of the included studies, of which 92.31% (12/13) were rated as \"low risk\" in less than 10% of the included studies. The incidence of \"low risk\" Chinese studies regarding performance bias, detection bias and reporting bias were lower than English studies. For foreign studies, more attention should be paid to selection bias, attrition bias, and reporting bias.\n\nConclusionWe identified limitations in the methodological quality of animal experiment studies published in China and abroad. We therefore suggest that it is necessary to take targeted measures to popularize the SYRCLEs risk of bias tool to effectively improve the design and implementation of animal experiments, and guide study development.

scientific communication and education↗
bioRxiv2019

A developmental gene regulatory network for invasive differentiation of the C. elegans anchor cell

Cellular invasion is a key part of development, immunity, and disease. Using the in vivo model of C. elegans anchor cell invasion, we characterize the gene regulatory network that promotes invasive differentiation. The anchor cell is initially specified in a stochastic cell fate decision mediated by Notch signaling. Previous research has identified four conserved transcription factors, fos-1a (Fos), egl-43 (EVI1/MEL), hlh-2 (E/Daughterless) and nhr-67 (NR2E1/TLX), that mediate anchor cell specification and/or invasive differentiation. Connections between these transcription factors and the underlying cell biology that they regulate is poorly understood. Here, using genome editing and RNA interference, we examine transcription factor interactions prior to and after anchor cell specification. During invasion we identify that egl-43, hlh-2, and nhr-67 function together in a type I coherent feed-forward loop with positive feedback. Conversely, prior to specification, these transcription factors function independent of one another to regulate LIN-12 (Notch) activity. Together, these results demonstrate that, although the same transcription factors can function in fate specification and differentiated cell behavior, a gene regulatory network can be rapidly re-wired to reinforce a post-mitotic, pro-invasive state.\n\nSUMMARY STATEMENTBasement membrane invasion by the C. elegans anchor cell is coordinated by a dynamic gene regulatory network encompassing cell cycle dependent and independent sub-circuits.

developmental biology↗
bioRxiv2019

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.\n\nType 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic {beta} cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

genetics↗
bioRxiv2019

Synergistic interplay between PHF8 and HER2 signaling contributes to breast cancer development and drug resistance

HER2 plays a critical role in tumorigenesis and is associated with poor prognosis of HER2-positive breast cancers. Although, anti-HER2 drugs show benefits in breast cancer therapy, de novo or acquired resistance often develop. Epigenetic factors have been increasingly targeted for therapeutic purposes, however, such mechanisms interacting with HER2 signaling are poorly understood. This study reports the synergistic interplay between histone demethylase PHF8 and HER2 signaling, i.e. PHF8 is elevated in HER2-positive breast cancers and is upregulated by HER2; PHF8 plays coactivator roles in regulating HER2 expression and HER2-driven epithelial-to-mesenchymal transition (EMT) markers and cytokines. The HER2-PHF8-IL-6 regulatory axis was proved both in cell lines and in the newly established MMTV-Her2/MMTV-Cre/Phf8flox/flox models, with which the oncogenic function of Phf8 in breast cancer in vivo was revealed for the first time. Furthermore, PHF8-IL-6 axis contributes to the resistance of Trastuzumab in vitro and may play a critical role in the infiltration of T-cells in HER2-driven breast cancers. This study reveals novel epigenetic mechanisms underlying HER2-driven cancer development and anti-HER2 drug resistance.

cancer biology↗