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  • Similarity in gene-regulatory networks suggests that cancer cells share characteristics of embryonic neural cells JOURNAL OF BIOLOGICAL CHEMISTRY Zhang, Z., Lei, A., Xu, L., Chen, L., Chen, Y., Zhang, X., Gao, Y., Yang, X., Zhang, M., Cao, Y. 2017; 292 (31): 12842–59

    Abstract

    Cancer cells are immature cells resulting from cellular reprogramming by gene misregulation, and redifferentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation. Here, we show that inhibition of the epigenetic modification enzyme enhancer of zeste homolog 2 (EZH2), histone deacetylases 1 and 3 (HDAC1 and -3), lysine demethylase 1A (LSD1), or DNA methyltransferase 1 (DNMT1), which all promote cancer development and progression, leads to postmitotic neuron-like differentiation with loss of malignant features in distinct solid cancer cell lines. The regulatory effect of these enzymes in neuronal differentiation resided in their intrinsic activity in embryonic neural precursor/progenitor cells. We further found that a major part of pan-cancer-promoting genes and the signal transducers of the pan-cancer-promoting signaling pathways, including the epithelial-to-mesenchymal transition (EMT) mesenchymal marker genes, display neural specific expression during embryonic neurulation. In contrast, many tumor suppressor genes, including the EMT epithelial marker gene that encodes cadherin 1 (CDH1), exhibited non-neural or no expression. This correlation indicated that cancer cells and embryonic neural cells share a regulatory network, mediating both tumorigenesis and neural development. This observed similarity in regulatory mechanisms suggests that cancer cells might share characteristics of embryonic neural cells.

    View details for DOI 10.1074/jbc.M117.785865

    View details for Web of Science ID 000407220100015

    View details for PubMedID 28634230

    View details for PubMedCentralID PMC5546026

  • Kruppel-like factor family genes are expressed during Xenopus embryogenesis and involved in germ layer formation and body axis patterning DEVELOPMENTAL DYNAMICS Gao, Y., Cao, Q., Lu, L., Zhang, X., Zhang, Z., Dong, X., Jia, W., Cao, Y. 2015; 244 (10): 1328–46

    Abstract

    Kruppel-like factors (Klfs) are a family of transcription factors consisting of 17 members in mammals, Klf1-Klf17, which are involved in fundamental cellular physiological procedures, such as cell proliferation, differentiation, and apoptosis. However, their functions in embryonic development have been poorly understood. Our previous study has demonstrated that the pluripotency factor Klf4 participates in germ layer formation and axis patterning of Xenopus embryos by means of the regulation of key developmental signals. In the present study, we further investigated comprehensively the expression and functions of the klf family genes, klf2, klf5, klf6, klf7, klf8, klf11, klf15, and klf17, during the embryogenesis of Xenopus laevis.Spatio-temporal expression analyses demonstrate that these genes are transcribed both maternally and zygotically in Xenopus embryos, and during organogenesis and tissue differentiation, they are localized to a variety of placodes and tissues. Gain and loss of function studies manifest that Klf factors play different roles in germ layer formation and body axis patterning. Moreover, each Klf factor exhibits distinct regulatory effects on the expression of genes that are essential for germ layer formation and body axis patterning.These results suggest that Klf factors are involved in the fine-tuning of these genes during early embryogenesis.

    View details for DOI 10.1002/dvdy.24310

    View details for Web of Science ID 000362089300013

    View details for PubMedID 26198170

  • JmjC Domain-containing Protein 6 (Jmjd6) Derepresses the Transcriptional Repressor Transcription Factor 7-like 1 (Tcf7l1) and Is Required for Body Axis Patterning during Xenopus Embryogenesis JOURNAL OF BIOLOGICAL CHEMISTRY Zhang, X., Gao, Y., Lu, L., Zhang, Z., Gan, S., Xu, L., Lei, A., Cao, Y. 2015; 290 (33): 20273–83

    Abstract

    Tcf7l1 (also known as Tcf3) is a bimodal transcription factor that plays essential roles in embryogenesis and embryonic and adult stem cells. On one hand, Tcf7l1 works as transcriptional repressor via the recruitment of Groucho-related transcriptional corepressors to repress the transcription of Wnt target genes, and, on the other hand, it activates Wnt target genes when Wnt-activated β-catenin interacts with it. However, how its activity is modulated is not well understood. Here we demonstrate that a JmjC-domain containing protein, Jmjd6, interacts with Tcf7l and derepresses Tcf7l. We show that Jmjd6 binds to a region of Tcf7l1 that is also responsible for Groucho interaction, therefore making it possible that Jmjd6 binding displaces the Groucho transcriptional corepressor from Tcf7l1. Moreover, we show that Jmjd6 antagonizes the repression effect of Tcf7l1 on target gene transcription and is able to enhance β-catenin-induced gene activation and that, vice versa, inhibition of Jmjd6 activity compromises gene activation in both cells and Xenopus early embryos. We also show that jmjd6 is both maternally and zygotically transcribed during Xenopus embryogenesis. Loss of Jmjd6 function causes defects in anterioposterior body axis formation and down-regulation of genes that are involved in anterioposterior axis patterning. The results elucidate a novel mechanism underlying the regulation of Tcf7l1 activity and the regulation of embryonic body axis formation.

    View details for DOI 10.1074/jbc.M115.646554

    View details for Web of Science ID 000359608900027

    View details for PubMedID 26157142

    View details for PubMedCentralID PMC4536435

  • Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear beta-Catenin DEVELOPMENTAL CELL Lu, L., Gao, Y., Zhang, Z., Cao, Q., Zhang, X., Zou, J., Cao, Y. 2015; 33 (6): 660–74

    Abstract

    In the absence of Wnt activation, cytosolic β-catenin is degraded through GSK3/CK1-mediated phosphorylation at the N terminus. Here, we show that, upon Wnt activation, the stability of nuclear β-catenin is regulated via methylation/demethylation. The protein lysine demethylases Kdm2a and Kdm2b regulate the turnover of non-phosphorylated β-catenin specifically within the nucleus via direct interaction with the fourth and fifth armadillo repeats. The lysine residues within this region are required for the methylation of non-phosphorylated β-catenin, which is demethylated by Kdm2a/b and subsequently ubiquitylated. During Xenopus embryogenesis, kdm2a/b genes are transcribed during early embryogenesis and are required for the specification of the body axis. Kdm2a/b knockdown in Xenopus embryos leads to increases in non-phosphorylated and methylated β-catenin, concurrent with the upregulation of β-catenin target genes. This mechanism is required for controlling the output of the Wnt/β-catenin signaling pathway to maintain normal cellular functions.

    View details for DOI 10.1016/j.devcel.2015.04.006

    View details for Web of Science ID 000356773900007

    View details for PubMedID 26004508

  • Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin Developmental Cell Lu*, L., Gao*, Y., Zhang, Z., Cao, Q., Zhang, X., Zou, J., Cao, Y. 2015
  • Klf4 is required for germ-layer differentiation and body axis patterning during Xenopus embryogenesis DEVELOPMENT Cao, Q., Zhang, X., Lu, L., Yang, L., Gao, J., Gao, Y., Ma, H., Cao, Y. 2012; 139 (21): 3950–61

    Abstract

    Klf4 is a transcription factor of the family of Kruppel-like factors and plays important roles in stem cell biology; however, its function during embryogenesis is unknown. Here, we report the characterization of a Klf4 homologue in Xenopus laevis during embryogenesis. Klf4 is transcribed both maternally and zygotically and the transcript is ubiquitous in embryos during germ-layer formation. Klf4 promotes endoderm differentiation in both Nodal/Activin-dependent and -independent manners. Moreover, Klf4 regulates anteroposterior body axis patterning via activation of a subset of genes in the Spemann organizer, such as Noggin, Dkk1 and Cerberus, which encode Nodal, Wnt and BMP antagonists. Loss of Klf4 function leads to the failure of germ-layer differentiation, the loss of responsiveness of early embryonic cells to inducing signals, e.g. Nodal/Activin, and the loss of transcription of genes involved in axis patterning. We conclude that Klf4 is required for germ-layer differentiation and body axis patterning by means of rendering early embryonic cells competent to differentiation signals.

    View details for DOI 10.1242/dev.082024

    View details for Web of Science ID 000309701300007

    View details for PubMedID 22992953