Yongfeng Shang

Peking University, Peping, Beijing, China

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Publications (54)496.83 Total impact

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    ABSTRACT: How loss-of-function of GATA3 contributes to the development of breast cancer is poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes including ZEB2 that are critically involved in epithelial-to-mesenchymal transition and cell invasion. We demonstrate that the GATA3/G9A/NuRD(MTA3) complex inhibits the invasive potential of breast cancer cells in vitro and suppresses breast cancer metastasis in vivo. Strikingly, the expression of GATA3, G9A, and MTA3 is concurrently downregulated during breast cancer progression, leading to an elevated expression of ZEB2, which, in turn, represses the expression of G9A and MTA3 through the recruitment of G9A/NuRD(MTA1). Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · Cancer cell
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    ABSTRACT: Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention. © 2015 Yan et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Mar 2015 · Genes & development
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    ABSTRACT: ATP-binding cassette (ABC) transporters are implicated in a diverse range of physiological and pathophysiological processes, such as cholesterol and lipid transportation and multidrug resistance. Despite the considerable efforts made in understanding of the cellular function of ABC proteins, the regulation mechanism of this type of protein is still poorly defined. Here we report the identification and functional characterization of a novel ATPase protein, protein associated with ABC transporters (PAAT), in humans. PAAT contains a nucleotide-binding domain (NBD)-like domain and a signal for intramitochondrial sorting. We showed that PAAT is localized in both the cytoplasm and the mitochondria and has an intrinsic ATPase activity. PAAT physically interacts with the 3 known mitochondrial inner membrane ABC proteins, ABCB7, ABCB8, and ABCB10, but not ABCB1, ABCB6, or ABCG2, and functionally regulates the transport of ferric nutrients and heme biosynthesis. Significantly, PAAT deficiency promotes cell death, reduces mitochondrial potential, and sensitizes mitochondria to oxidative stress-induced DNA damages. Our experiments revealed that PAAT is a novel ATPase and a trans-regulator of mitochondrial ABC transporters that plays an important role in the maintenance of mitochondrial homeostasis and cell survival.-Yang, X., Yang, J., Li, L., Sun, L., Yi, X., Han, X., Si, W., Yan, R., Chen, Z., Xie, G., Li, W., Shang, Y., Liang, J. PAAT, a novel ATPase and trans-regulator of mitochondrial ABC transporters, is critically involved in the maintenance of mitochondrial homeostasis.
    No preview · Article · Jul 2014 · The FASEB Journal
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    ABSTRACT: Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.
    Full-text · Article · Jul 2014 · Molecular Cell
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    ABSTRACT: Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is controlled by epigenetic mechanisms is not fully understood. Here we report the identification and characterization of lysine-specific histone demethylase 5B (KDM5B), a member of the JmjC domain-containing histone demethylases, as an important player in multiple aspects of DNA double-strand break (DSB) response in human cells. We found that KDM5B becomes enriched in DNA-damage sites after ironizing radiation and endonuclease treatment in a poly(ADP ribose) polymerase 1- and histone variant macroH2A1.1-dependent manner. We showed that KDM5B is required for efficient DSB repair and for the recruitment of Ku70 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively. Significantly, KDM5B deficiency disengages the DNA repair process, promotes spontaneous DNA damage, activates p53 signaling, and sensitizes cells to genotoxic insults. Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability, adding to the understanding of the roles of epigenetics in the maintenance of genetic fidelity.
    Preview · Article · Apr 2014 · Proceedings of the National Academy of Sciences
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    Cai Qi · Shumeng Liu · Rui Qin · Yu Zhang · Guoqiang Wang · Yongfeng Shang · Yun Wang · Jing Liang
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    ABSTRACT: Dendritic arborization is one of the key determinants of precise circuits for information processing in neurons. Unraveling the molecular mechanisms underlying dendrite morphogenesis is critical to understanding the establishment of neuronal connections. Here, using gain- and loss-of-function approaches, we defined the chromodomain protein and transcription corepressor chromodomain Y-like (CDYL) protein as a negative regulator of dendrite morphogenesis in rat/mouse hippocampal neurons both in vitro and in vivo. Overexpressing CDYL decreased, whereas knocking it down increased, the dendritic complexity of the primary cultured rat neurons. High-throughput DNA microarray screening identified a number of CDYL downstream target genes, including the brain-derived neurotrophic factor (BDNF). Knock-down of CDYL in neuronal cells led to increased expression of BDNF, which is primarily responsible for CDYL's effects on dendrite patterns. Mechanistically, CDYL interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), directly and recruits the H3K27 methyltransferase activity to the promoter region of the BDNF gene. In doing so, CDYL and EZH2 coordinately restrict dendrite morphogenesis in an interdependent manner. Finally, we found that neural activity increased dendritic complexity through degradation of CDYL protein to unleash its inhibition on BDNF. These results link, for the first time, the epigenetic regulators CDYL and EZH2 to dendrite morphogenesis and might shed new light on our understanding of the regulation of the neurodevelopment.
    Preview · Article · Mar 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.
    Full-text · Article · Mar 2014 · PLoS Biology
  • Jing Liang · Yongfeng Shang
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    ABSTRACT: Metastasis refers to the process that cancer cells leave their primary tumor mass, break into blood and lymphatic vessels, and travel to distant organ sites throughout the body where they may establish new colonies. Metastasis is responsible for 90 % of cancer mortality. Increasing evidence suggest that epigenetic mechanisms, such as DNA methylation and histone modifications, play an important role in mediating the invasion-metastasis cascade. Targeting deregulated epigenetic modification enzymes by small-molecule inhibitors is a promising therapeutic strategy for the treatment of metastatic cancers.
    No preview · Chapter · Jan 2014
  • Peiwei Huangyang · Yongfeng Shang
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    ABSTRACT: Epithelial-mesenchymal transition (EMT)is a vital process implemented inembryo development, organ fibrosis, and cancer metastasis.Several transcriptional factors and signaling pathways impinge on the transcriptional program of the cell, leading to the change of cell phenotype without alteration of genotype.Accumulating evidence suggests that epigenetic mechanisms play important roles in inducing EMT and orchest rating the heredity and reversibility of EMT. In this review, we discuss how DNA methylation, histone modifications, and microRNAs (miRNAs) act in a concertedmanner to regulate EMT. 'Epigenetic therapies'-inhibitors of DNA methyltransferases and histone deacetylases as well as microRNA are emerging as promising agents for cancer intervention.
    No preview · Article · Oct 2013 · Current cancer drug targets
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    ABSTRACT: SET8 (SET domain containing 8) is a histone H4 lysine 20 (H4K20)-specific monomethyltransferase in higher eukaryotes that exerts diverse functions in transcription regulation, DNA repair, tumor metastasis, and genome integrity. The activity of SET8 is tightly controlled during cell cycle through post-translational modifications, including ubiquitination, phosphorylation, and sumoylation. However, how the expression of SET8 is regulated is not fully understood. Here, we report that microRNA-7 is a negative regulator of SET8. We demonstrated that microRNA-7 inhibits H4K20 monomethylation and suppresses epithelial-mesenchymal transition and the invasive potential of breast cancer cells. We showed that microRNA-7 promotes spontaneous DNA damages and sensitizes cells to induced DNA damages. Our experiments provide a molecular mechanism for the regulation of SET8 and extend the biological function of microRNA-7 to DNA damage response, supporting the pursuit of microRNA-7 as a potential target for breast cancer intervention.
    Preview · Article · May 2013 · Journal of Biological Chemistry
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    Xiaohan Yang · Lei Li · Jing Liang · Lei Shi · Jianguo Yang · Xia Yi · Di Zhang · Xiao Han · Na Yu · Yongfeng Shang
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    ABSTRACT: Faithful repair of DNA double-strand breaks is vital to the maintenance of genome integrity and proper cell functions. Histone modifications, such as reversible acetylation, phosphorylation, methylation, and ubiquitination, which collectively contribute to the establishment of distinct chromatin states, play important roles in the recruitment of repair factors to the sites of double-strand breaks. Here we report that histone acetyltransferase 1 (HAT1), a classical B type histone acetyltransferase responsible for acetylating the N-terminal tail of newly synthesized histone H4 in the cytoplasm, is a key regulator of DNA repair by homologous recombination in the nucleus. We found that HAT1 is required for the incorporation of H4K5/K12-acetylated H3.3 at sites of double-strand breaks through its HIRA-dependent histone turnover activity. Incorporated histones with specific chemical modifications facilitate subsequent recruitment of RAD51, a key repair factor in mammalian cells, to promote efficient homologous recombination. Significantly, depletion of HAT1 sensitized cells to DNA damage compromised the global chromatin structure, inhibited cell proliferation, and induced cell apoptosis. Our experiments uncovered a role for HAT1 in DNA repair in higher eukaryotic organisms and provide a mechanistic insight into the regulation of histone dynamics by HAT1.
    Preview · Article · May 2013 · Journal of Biological Chemistry
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    ABSTRACT: We reported that Cullin4B-Ring E3 ligase complex (CRL4B) is physically associated with Polycomb-repressive complex 2 (PRC2). We showed that CRL4B possesses an intrinsic transcription repressive activity by promoting H2AK119 monoubiquitination. Ablation of Cul4b or depletion of CUL4B, the main component of CRL4B, resulted in loss of not only H2AK119 monoubiquitination but also H3K27 trimethylation, leading to derepression of target genes that are critically involved in cell growth and migration. We demonstrated that CUL4B promotes cell proliferation, invasion, and tumorigenesis in vitro and in vivo and found that its expression is markedly upregulated in various human cancers. Our data indicate that CUL4B promotes tumorigenesis, supporting the pursuit of CUL4B as a target for cancer therapy.
    Full-text · Article · Dec 2012 · Cancer cell
  • Jing Liang · Yongfeng Shang
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    ABSTRACT: Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to the existing antiestrogen therapy. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    No preview · Article · Oct 2012 · Annual Review of Physiology
  • Yan Wang · Yongfeng Shang
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is vital for morphogenesis during embryonic development and is also critical for the conversion of early stage tumors into invasive malignancies. Several key inducers of EMT are transcription factors that repress the expression of E-cadherin, whose loss is a hallmark of EMT. Epigenetic regulation encompasses three types of changes: DNA methylation, histone modifications, and microRNAs, each of which has been shown to play a key role in controlling epithelial-mesenchymal transition and cancer metastasis. As we gain deeper understanding of epigenetic mechanisms controlling EMT processes and orchestrating all the metastatic steps, we broaden the therapeutic potentials of epigenetic drugs, such as DNA demethylating drugs and histone deacetylase/demethylase inhibitors, which can act upon metastasis-related genes, restoring their expression and biological functions.
    No preview · Article · Aug 2012 · Experimental Cell Research
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    ABSTRACT: Despite the identification of the 43 kDa transactive response DNA-binding protein (TDP-43) as a major pathological signatory protein in a wide range of neurodegenerative diseases, the mechanistic role of TDP-43 in neurodegenerative disorders is still poorly understood. Here, we report that TDP-43 is physically associated with fragile X mental retardation protein (FMRP) and Staufen (STAU1) to form a functional complex. Differential microarray analysis revealed that the expression of a collection of functionally important genes including Sirtuin (SIRT1) is regulated by this complex. RNA-immunoprecipitation (RIP) and RNA pull-down assays demonstrated that TDP-43/FMRP/STAU1 specifically binds to the 3′-UTR of SIRT1 mRNA, and that knockdown the expression of any one of these three proteins resulted in the reduction of SIRT1 mRNA and protein. SIRT1 is implicated in double-stranded DNA break repair and is required for cell survival. Indeed, depletion of TDP-43/FMRP/STAU1 sensitizes cells to apoptosis and DNA damages. Collectively, our results revealed a molecular mechanism for the cellular function of TDP-43 and might shed new light on the understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.
    Full-text · Article · May 2012 · Journal of Biological Chemistry
  • Xia Yi · Mei Hong · Bin Gui · Zhe Chen · Lei Li · Guojia Xie · Jing Liang · Xiaocheng Wang · Yongfeng Shang
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    ABSTRACT: Ccr4d is a new member of the Ccr4 (carbon catabolite repression 4) family of proteins that are implicated in the regulation of mRNA stability and translation through mRNA deadenylation. However, Ccr4d is not believed to be involved in mRNA deadenylation. Thus, its biological function and mechanistic activity remain to be determined. Here, we report that Ccr4d is broadly expressed in various normal tissues, and the expression of Ccr4d is markedly down-regulated during cell cycle progression. We showed that Ccr4d inhibits cell proliferation and induces cell cycle arrest at G1 phase. Our experiments further revealed that Ccr4d regulates the expression of p21 in a p53-independent manner. Mechanistic studies indicated that Ccr4d strongly bound to the 3′-UTR of p21 mRNA, leading to the stabilization of p21 mRNA. Interestingly, we found that the expression of Ccr4d is down-regulated in various tumor tissues. Collectively, our data indicate that Ccr4d functions as an anti-proliferating protein through the induction of cell cycle arrest via a p21-dependent and p53-independent pathway and suggest that Ccr4d might have an important role in carcinogenesis.
    No preview · Article · Apr 2012 · Journal of Biological Chemistry
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    ABSTRACT: The impact of methylation of the 3'-untranslated region (UTR) of a messenger RNA (mRNA) remains largely unknown. Here we show that NSun2, a transfer RNA methyltransferase, inhibits the turnover of p16(INK4) mRNA. Knockdown of NSun2 reduces p16 expression by shortening the half-life of the p16 mRNA, while overexpression of NSun2 stabilizes the p16 mRNA. In vitro methylation assays show that NSun2 methylates the p16 3'UTR at A988. Knockdown of NSun2 reduces the stability of the EGFP-p16 chimeric reporter transcripts bearing wild-type p16 3'UTR, but not p16 3'UTR with a mutant methylation site. Methylation by NSun2 prevents the association of p16 3'UTR with HuR, AUF1 and Ago2/RISC, and prevents the recruitment of EGFP-p16 3'UTR chimeric transcripts to processing bodies. In response to oxidative stress, NSun2 is essential for elevating p16 expression levels. We conclude that NSun2-mediated methylation of the p16 3'UTR is a novel mechanism to stabilize p16 mRNA.
    Full-text · Article · Mar 2012 · Nature Communications
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    Dandan Wang · Jing Liang · Yu Zhang · Bin Gui · Feng Wang · Xia Yi · Luyang Sun · Zhi Yao · Yongfeng Shang
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    ABSTRACT: Apoptosis-inducing factor (AIF) is a caspase-independent death effector. Normally residing in the mitochondrial intermembrane space, AIF is released and translocated to the nucleus in response to proapoptotic stimuli. Nuclear AIF binds to DNA and induces chromatin condensation and DNA fragmentation, characteristics of apoptosis. Until now, it remained to be clarified how the mitochondrial-nuclear translocation of AIF is regulated. Here we report that steroid receptor coactivator-interacting protein (SIP) interacts directly with AIF in mitochondria and specifically inhibits caspase-independent and AIF-dependent apoptosis. Challenging cells with apoptotic stimuli leads to rapid degradation of SIP, and subsequently AIF is liberated from mitochondria and translocated to the nucleus to induce apoptosis. Together, our data demonstrate that SIP is a novel regulator in caspase-independent and AIF-mediated apoptosis.
    Full-text · Article · Feb 2012 · Journal of Biological Chemistry
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    ABSTRACT: Self-association of a protein to form dimer and oligomer is a general theme in biological control mechanism, and is increasingly understood to be an important step in many cellular processes, including signaling transduction, protein degradation and transcriptional regulation. Previously, we cloned and functionally characterized a gene encoded for ZIP (zinc finger and G-patch domain-containing protein). We showed that ZIP is a novel transcription repressor that regulates, through recruitment of the nucleosome remodeling and deacetylase (NuRD) complex, a collection of functionally important genes including the epidermal growth factor receptor (EGFR) oncogene. The important role ZIP plays in controlling cell proliferation and carcinogenesis highlights the need for a detailed understanding of the finely mechanisms by which ZIP is regulated. Here, we report that ZIP forms homodimers in vitro and in vivo through its C-terminal domains. We demonstrated that ZIP dimerization promotes its transcriptional repressive activity and is essential for its DNA binding. We showed that enforced dimerization of ZIP suppresses EGFR expression, leading to the delay of cell cycle progression and the inhibition of breast cancer cell proliferation. Thus, our results revealed that dimerization is crucial for is transcriptional repressive function and biological activity and provided a finely tuned means for the regulation the expression of EGFR oncogene. These may shed new light on the EGFR-related breast carcinogenesis and offer a potential new target for breast cancer therapy.
    Full-text · Article · Feb 2012 · The international journal of biochemistry & cell biology
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    Fen Yang · Luyang Sun · Qian Li · Xiao Han · Liandi Lei · Hua Zhang · Yongfeng Shang
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    ABSTRACT: SET8 is implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression, and development. As such, it is predicted that SET8 might be involved in the development and progression of tumour. However, whether and how SET8 might be implicated in tumourigenesis is currently unknown. Here, we report that SET8 is physically associated with TWIST, a master regulator of epithelial-mesenchymal transition (EMT). We demonstrated that SET8 and TWIST are functionally interdependent in promoting EMT and enhancing the invasive potential of breast cancer cells in vitro and in vivo. We showed that SET8 acts as a dual epigenetic modifier on the promoters of the TWIST target genes E-cadherin and N-cadherin via its H4K20 monomethylation activity. Significantly, in breast carcinoma samples, SET8 expression is positively correlated with metastasis and the expression of TWIST and N-cadherin and negatively correlated with E-cadherin. Together, our experiments revealed a novel role for SET8 in tumour invasion and metastasis and provide a molecular mechanism underlying TWIST-promoted EMT, suggesting SET8 as a potential target for intervention of the metastasis of breast cancer.
    Full-text · Article · Jan 2012 · The EMBO Journal

Publication Stats

2k Citations
496.83 Total Impact Points

Institutions

  • 2008-2015
    • Peking University
      Peping, Beijing, China
  • 2003-2014
    • Peking University Health Science Center
      • Department of Biochemistry and Molecular Biology
      Peping, Beijing, China
  • 2012
    • Tianjin Medical University
      T’ien-ching-shih, Tianjin Shi, China
  • 2010
    • Changzhi Medical College
      Shanxi, Liaoning, China