Regulation of CD133 by HDAC6 Promotes β-Catenin Signaling to Suppress Cancer Cell Differentiation

Mak, Anthony B.; Nixon, Allison M.L.; Kittanakom, Saranya; Stewart, Jocelyn M.; Chen, Ginny I.; Ćurak, Jasna; Gingras, Anne‐Claude; Mazitschek, Ralph; Neel, Benjamin G.; Štagljar, Igor; Moffat, Jason

doi:10.1016/j.celrep.2012.09.016

Cited by 169 publications

(183 citation statements)

References 47 publications

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“…In the present study, although TSA enhanced the transcription level of β-catenin in BGC-823 and MCF-7 cells, the protein levels were reduced following TSA treatment (Fig. 5), which was consistent with previous studies reporting that HDAC6 is required for β-catenin activation in colon cancer cells (20,21). Whether TSA-mediated EMT induction and inhibition, elevation of β-catenin mRNA levels and inhibition of β-catenin protein levels are associated with other signaling pathways, such as the decorin-β-catenin-E-cadherin signaling pathway (22), remains unclear and is currently under investigation.…”

Section: Tsa Increases the Expression Levels Of Mesenchymal Markers Asupporting

confidence: 82%

Trichostatin A induces mesenchymal-like morphological change and gene expression but inhibits migration and colony formation in human cancer cells

Han

Yang

et al. 2014

Molecular Medicine Reports

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Abstract. Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl from lysine residues in histones and other proteins, which results in gene transcriptional repression and subsequent changes in signaling events. HDACs inhibitors (HDACIs) have been used to reverse the aberrant epigenetic changes associated with cancer. However, the effects of HDACIs on epithelial-mesenchymal transition (EMT) in human cancer cells remain unclear. EMT is a fundamental process governing morphogenesis in multicellular organisms and promotes cancer invasion and metastasis. In this study, human cancer cells were treated with the HDACI trichostatin A (TSA). TSA was found to induce mesenchymal-like morphological changes in BGC-823 human gastric cancer and MCF-7 breast cancer cells, and increase the expression levels of the mesenchymal markers Vimentin and Twist. However, the expression levels of the epithelial cell marker E-cadherin were also increased in response to TSA treatment, while cell migration was reduced by TSA. Furthermore, TSA decreased cancer cell colony formation in BGC-823 and MCF-7 cells, and led to the deregulation of β-catenin, a critical signaling molecule involved in EMT. In conclusion, the results suggested that TSA exhibits dual functions in EMT induction and inhibition in human cancer cells, but the detailed mechanisms require further investigation.

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Section: Tsa Increases the Expression Levels Of Mesenchymal Markers Asupporting

confidence: 82%

Trichostatin A induces mesenchymal-like morphological change and gene expression but inhibits migration and colony formation in human cancer cells

Han

Yang

et al. 2014

Molecular Medicine Reports

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“…Caco-2 cells can differentiate into an enterocyte-like phenotype, either with treatment by HDAC inhibitors or spontaneously with overconfluence, characterized by a polarized monolayer and the expression of cytokeratin 20 (KRT20) and the brush-border enzymes such as sucrase-isomaltase (SI). 21,22 To determine whether βHB has a role in human intestinal cell differentiation, Caco-2 cells were treated with βHB for 48 h and the mRNA levels of the enterocyte markers SI and KRT20 were determined. As shown in Figure 1a, treatment of Caco-2 cells with βHB-induced SI and KRT20 mRNA expression, suggesting that βHB increases enterocyte differentiation.…”

Section: Resultsmentioning

confidence: 99%

Ketogenesis contributes to intestinal cell differentiation

et al. 2016

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The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.

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“…Besides histones, p300 catalyses many nonhistone proteins, including β-catenin (Wolf et al, 2002). Indeed, Li et al reported that acetylation at Lysine 49 was required for β-catenin phosphorylation (Li et al, 2008), whereas downregulation of histone deacetylation resulted in β-catenin degradation in colon cancer cells Mak et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

Han

Ji²,

Dong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The epithelial to mesenchymal transition (EMT) is a key step during embryonic morphogenesis and plays an important role in drug resistance and metastasis in diverse solid tumors. We previously reported that 48 h treatment of anti-cancer drug doxorubicin could induce EMT in human gastric cancer BGC-823 cells. However, the long term effects of this transient drug treatment were unknown. In this study we found that after 48 h treatment with 0.1 μg/ml doxorubicin, most cells died during next week, while a minor population of cells survived and formed colonies. We propagated the surviving cells in drug free medium and found that these long term cultured drug survival cells (abbreviated as ltDSCs) retained a mesenchymal-like cell morphology, and expressed high levels of EMT-related molecules such as vimentin, twist and β-catenin. The expression of chromatin reprogramming factors, Oct4 and c-myc, were also higher in ltDSCs than parental cells. We further demonstrated that the protein level of p300 was upregulated in ltDSCs, and inhibition of p300 by siRNA suppressed the expression of vimentin. Moreover, the ltDSCs had higher colony forming ability and were more drug resistant when compared to parental cells. Our results suggested that an epigenetic mechanism is involved in the EMT of ltDSCs.

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Regulation of CD133 by HDAC6 Promotes β-Catenin Signaling to Suppress Cancer Cell Differentiation

Cited by 169 publications

References 47 publications

Trichostatin A induces mesenchymal-like morphological change and gene expression but inhibits migration and colony formation in human cancer cells

Trichostatin A induces mesenchymal-like morphological change and gene expression but inhibits migration and colony formation in human cancer cells

Ketogenesis contributes to intestinal cell differentiation

An Epigenetic Mechanism Underlying Doxorubicin Induced EMT in the Human BGC-823 Gastric Cancer Cell

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