Interplay between HDAC3 and WDR5 Is Essential for Hypoxia-Induced Epithelial-Mesenchymal Transition

Wu, Min; Tsai, Ya Ping; Yang, Muh Hwa; Huang, Chih Chia; Chang, Shun‐Hsyung; Chang, Cheng; Teng, Shu-Chun; Wu, Kou Juey

doi:10.1016/j.molcel.2011.07.012

Cited by 242 publications

(252 citation statements)

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“…Previous analyses of the migratory transcriptome have tended to rely on microarrays of cell populations, such as populations of border cells in Drosophila (7,8) and heart cells in Ciona (9). More recently, RNA-seq (10) and functional genomics (11) have been used to identify mammalian genes involved in the transition to invasive mesenchymal cell types. In C. elegans, it should be possible to combine such RNA-seq with single-cell analysis to achieve a comprehensive inventory of genes involved in migration, with precise temporal resolution.…”

mentioning

confidence: 99%

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Schwarz

Kato

Sternberg

2012

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

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In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi-treated L4 larvae. We observed expression of 8,000-10,000 genes in the linker cell, 22-25% of which were up-or downregulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67-dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.major sperm protein | nematode development | transcriptional profiling | twin pore potassium channels | conserved uncharacterized proteins C ell migration is pervasive in animal development and is also an unwanted part of human cancer. Several different varieties of cell migration, ranging from social protozoa to the human immune system, have been extensively studied (1), but there remains a need for detailed analysis of the different components of migration in a simple cell type that can be exhaustively probed through anatomy, genetics, and genomics. We have undertaken to develop the linker cell (LC) of Caenorhabditis elegans as such a model. The LC is a single cell, attached to the front of a proliferating male gonad, which carries out a stereotypic, long-range migration to generate the shape of the mature gonad (Fig. 1A). During 25 h of the second to fourth larval stages (L2 through L4), the LC moves anteriorly along the ventral body wall, turns dorsally, proceeds posteriorly, switches sides once more to the ventral bodywall, continues posteriorward, reaches the cloaca, and eventually dies (2-4). Throughout this process, the proliferating and lengthening male gonad follows the LC's path to the cloaca. Stage-specific changes occur during the middle to late stages of migration (L3 and L4 larval stages): the LC changes shape from a spheroid to a pointed ellipsoid; it increases its speed of migration; and the netrin receptor gene unc-5 is down-regulated within the LC, which causes it to switch body walls ventrally ( Fig. 1A; ref. 3). These changes between the L3 and L4 stages require the orphan nuclear receptor NHR-67, whose orthologs TAILLESS and TLX...

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mentioning

confidence: 99%

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Schwarz

Kato

Sternberg

2012

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

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“…We found that HDAC3Y298F (an HDAC3 mutant devoid of deacetylase activity; ref. 45) reinforced, as HDAC3 WT, the WWOX-BCL9-2 association, and that the general inhibitor of histone deacetalyses TSA did not impair the ability of HDAC3 to promote WWOX-BCL9-2 interaction in 293 cells (Fig. 7A and data not shown).…”

Section: Hdac3 Promotes the Wwox-bcl9-2 Association Independently Of mentioning

confidence: 75%

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

El-Hage

Petitalot

Monsoro-Burq

et al. 2015

Molecular Cancer Research

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The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/b-catenin pathway by preventing the nuclear import of disheveled 2 (DVL2) in human breast cancer cells. Here, it is revealed that WWOX also interacts with the BCL9-2, a cofactor of the Wnt/b-catenin pathway, to enhance the activity of the b-catenin-TCF/LEF (T-cell factor/ lymphoid enhancer factors family) transcription factor complexes. By using both a luciferase assay in MCF-7 cells and a Xenopus secondary axis induction assay, it was demonstrated that WWOX inhibits the BCL9-2 function in Wnt/b-catenin signaling. WWOX does not affect the BCL9-2-b-catenin association and colocalizes with BCL9-2 and b-catenin in the nucleus of the MCF-7 cells. Moreover, WWOX inhibits the b-catenin-TCF1 interaction. Further examination found that HDAC3 associates with BCL9-2, enhances the inhibitory effect of WWOX on BCL9-2 transcriptional activity, and promotes the WWOX-BCL9-2 interaction, independent of its deacetylase activity. However, WWOX does not influence the HDAC3-BCL9-2 interaction. Altogether, these results strongly indicate that nuclear WWOX interacts with BCL9-2 associated with b-catenin only when BCL9-2 is in complex with HDAC3 and inhibits its transcriptional activity, in part, by inhibiting the b-catenin-TCF1 interaction. The promotion of the WWOX-BCL9-2 interaction by HDAC3, independent of its deacetylase activity, represents a new mechanism by which this HDAC inhibits transcription. Implications:The inhibition of the transcriptional activity of BCL9-2 by WWOX and HDAC3 constitutes a new molecular mechanism and provides new insight for a broad range of cancers.

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“…Cells were cross-linked 46 with 2% formaldehyde for 10 min and stopped by adding glycine to a final concentration of 0.125 M. Fixed cells were washed twice with Tris-buffered saline (TBS) (20 mM Tris, pH 7.5, 150 mM NaCl) and collected in 5 ml of SDS buffer (50 mM Tris, pH 8.0, 0.5% SDS, 100 mM NaCl, 5 mM EDTA and protease inhibitors). Cells were pelleted by centrifugation and suspended in 2 ml of immunoprecipitation (IP) buffer (100 mM Tris, pH 8.6, 0.3% SDS, 1.7% Triton X-100 and 5 mM EDTA).…”

Section: Methodsmentioning

confidence: 99%

“…The sample processing and 11,24,46 IHC procedure for determining the immunoreactivity of Twist1, Jagged1 and KLF4 were described as the following. The paraffin-embedded tissue specimens were de-paraffinized in xylene, rehydrated through 100, 90, 70, 50% ethanol and rinsed in PBS buffer.…”

Section: Oecm1-mentioning

confidence: 99%

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

et al. 2014

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The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/ Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition.

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Interplay between HDAC3 and WDR5 Is Essential for Hypoxia-Induced Epithelial-Mesenchymal Transition

Cited by 242 publications

References 50 publications

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

Functional transcriptomics of a migrating cell in Caenorhabditis elegans

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

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