Cell Fate Determination Factor Dachshund Reprograms Breast Cancer Stem Cell Function

Wu, Kongming; Jiao, Xuanmao; Li, Zhaoming; Katiyar, Sanjay; Casimiro, Mathew C.; Yang, Wancai; Zhang, Qiong; Willmarth, Nicole E.; Chepelev, Iouri; Crosariol, Marco; Zhang, Wei; Hu, Junbo; Zhao, Keji; Pestell, Richard G.

doi:10.1074/jbc.m110.148395

Cited by 79 publications

(99 citation statements)

References 44 publications

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“…As far as we know, this is the first study showing loss of DACH1 gene function in tumor cells at the genomic level. Our observation supports recent studies indicating that DACH1 scarcely expressed in tumor-initiating cells and such low expression correlated with poor prognosis of breast cancers (17,18,47). We showed that DACH1 expression decreases proliferation of glioma cells and suppresses tumorigenicity through inhibition of bFGF-dependent spheroid formation.…”

Section: Dach1-spanning Region Is Indicated As a Target Of Copy Numbesupporting

confidence: 80%

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Watanabe

Ogiwara

Ehata³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.neural differentiation | gliomagenesis

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Section: Dach1-spanning Region Is Indicated As a Target Of Copy Numbesupporting

confidence: 80%

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Watanabe

Ogiwara

Ehata³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…An impressive observation has shown that CSCs exist in single cancer cell-derived cultures, which reveals the flexibility of the cancer cell status in tumors due to genomic instability in cancer cells (23,24). In addition, the dedifferentiation of cancer cells can be induced by different environmental cues, such as inflammation, hypoxia, and serum deprivation, through epigenetic or genetic regulation (25). Recently, epithelial-to-mesenchymal transition (EMT) has been broadly showed to convert mature cancer cells into CSCs (26,27), which is mediated by EMTassociated genes and microRNAs (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

et al. 2013

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Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133 þ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133 þ cells has not been investigated methodically. In this study, we revealed that CD133 þ lung cancer cells labeled by a human CD133

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“…DACH1 has an instructive role in preventing proliferation, because its expression inhibits oncogenic transformation of breast epithelial cell lines and breast tumor stem cell expansion (Wu et al, 2011). Based on the high levels of conservation between Drosophila Yki and Dac and their human counterparts, our work suggests that mammalian DACH proteins might also inactivate the transcriptional activity of YAP and/or TAZ (also known as WWTR1) on a subset of target genes by interacting with specific YAP or TAZ DNA-binding partners.…”

Section: Dac or Dachs And Cancermentioning

confidence: 99%

“…DACH1 expression is reduced in prostate, breast and uterine cancer, correlating with tumor progression and invasiveness . DACH1 inhibits oncogene-mediated breast oncogenesis in part by repressing cyclin D1 through a c-Jun DNA-binding partner (Sunde et al, 2006;Wu et al, 2006Wu et al, , 2007, and it prevents breast tumor stem cell expansion (Wu et al, 2011). Moreover, DACH1 expression inhibits DNA synthesis and growth in colony-forming assays in breast and prostate cancer cells and has been shown to restrict the transcriptional activity of the hormone receptors by recruiting the NCoR and HDAC1 co-repressors ).…”

Section: Introductionmentioning

confidence: 99%

The retinal determination genedachshundrestricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex

2015

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The Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie-dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the YorkieHomothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ.

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Cell Fate Determination Factor Dachshund Reprograms Breast Cancer Stem Cell Function

Cited by 79 publications

References 44 publications

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

The retinal determination genedachshundrestricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex

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