Slug is temporally regulated by cyclin E in cell cycle and controls genome stability

Wang, W. L.; Huang, Hsu-Cheng; Kao, Shu Huei; Hsu, Yen‐Chu; Wang, Y. T.; Li, K. C.; Chen, Yu‐Ju; Yu, Sung-Liang; Wang, S. P.; Hsiao, Tzu Hung; Hong, Tse-Ming

doi:10.1038/onc.2014.58

Cited by 34 publications

(27 citation statements)

References 30 publications

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“…Moreover, the Daxx and ATRX complex is required for histone H3.3 heterochromatin deposition and accounts for H3.3 serine-31 phosphorylation; these mechanisms are abolished by disrupting the Daxx–ATRX complex5961. Recent findings have shown that the Slug protein is tightly regulated at the posttranslational level and its transcriptional activity is negatively controlled by several kinases via a phosphodegron mechanism416263. To address this, we evaluated whether Daxx-bound Slug is subsequently targeted for degradation.…”

Section: Discussionmentioning

confidence: 99%

Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis

Lin

Wang

et al. 2016

Nat Commun

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Hypoxia is a major driving force of cancer invasion and metastasis. Here we show that death domain-associated protein (Daxx) acts to negatively regulate hypoxia-induced cell dissemination and invasion by inhibiting the HIF-1α/HDAC1/Slug pathway. Daxx directly binds to the DNA-binding domain of Slug, impeding histone deacetylase 1 (HDAC1) recruitment and antagonizing Slug E-box binding. This, in turn, stimulates E-cadherin and occludin expression and suppresses Slug-mediated epithelial–mesenchymal transition (EMT) and cell invasiveness. Under hypoxic conditions, stabilized hypoxia-inducible factor (HIF)-1α downregulates Daxx expression and promotes cancer invasion, whereas re-expression of Daxx represses hypoxia-induced cancer invasion. Daxx also suppresses Slug-mediated lung cancer metastasis in an orthotopic lung metastasis mouse model. Using clinical tumour samples, we confirmed that the HIF-1α/Daxx/Slug pathway is an outcome predictor. Our results support that Daxx can act as a repressor in controlling HIF-1α/HDAC1/Slug-mediated cancer cell invasion and is a potential therapeutic target for inhibition of cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis

Lin

Wang

et al. 2016

Nat Commun

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“…The 2D cultured cells also maintained a high level of cellular homogeneity, where~96% of 4T1 cells persisted in an epithelial cell state. Carcinomas of different tissue origin, including lung and gastric, have been documented to undergo EMT, as characterized by a loss in epithelial behaviors like cell polarity and cell-cell adhesion [25] and a decreased proliferation in cells up-regulating EMT genes [26].…”

Section: Discussionmentioning

confidence: 99%

“…using Loupe Cell Browser (10× Genomics) and Seurat (26). The Cell Ranger Single-Cell Software Suite was used to perform sample demultiplexing, barcode processing, and single-cell 3 gene counting.…”

Section: The 4t1-bfp Generationmentioning

confidence: 99%

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Hum

Sebastian

Gilmore

et al. 2020

Cancers

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Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations.

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“…SNAI2 alone sometimes is sufficient to induce EMT, and it is essential for Twist-induced EMT (42). SNAI2 has also been implicated in cancer cell stemness, cell cycle regulation, proliferation, apoptosis, chemotherapy resistance as well as invasion and metastasis (43)(44)(45)(46)(47)(48)(49). SNAI2 expression and activity has been associated with poor clinical outcome in multiple cancer types, including breast cancer (50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

et al. 2019

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Epithelial‐mesenchymal transition (EMT) is a critical process implicated in the initial stage of cancer metastasis, which is the major cause of tumor recurrence and mortality. Although key transcription factors that regulate EMT, such as snail family transcriptional repressor 2 (SNAI2), are well characterized, the upstream signaling pathways controlling these transcriptional mediators are largely unknown, which limits therapeutic strategies. Sphingosine 1–phosphate (S1P) is a bioactive lipid mediator, generated by sphingosine kinases (SPHK1 and SPHK2), that mainly exerts its effects by binding to the following 5 GPCRs: S1P1 to S1P5. S1P signaling has been reported to regulate different aspects of cancer progression including cell proliferation, apoptosis, and migration; nevertheless, its role in cancer metastasis, specifically via EMT, is not established. Here we show that SPHK1 expression correlates significantly with EMT score in breast cancer cell lines, and with SNAI2 in patient‐derived breast tumors. Cell‐based assays demonstrate that S1P can rapidly up‐regulate the expression of SNAI2 in breast cancer cells via the activation of cognate receptors S1P2 and S1P3. Knockdown studies suggest that S1P2 and S1P3 mediate this effect by activating myocardin‐related transcription factor A (MRTF‐A) and yes‐associated protein (YAP), respectively. Michigan Cancer Foundation 7 cells stably overexpressing S1P2 or S1P3 exhibit a more invasive phenotype, when compared to control cells. Taken together, our findings suggest that S1P produced by SPHK1 induces SNAI2 expression via S1P2‐YAP and S1P3‐MRTF‐A pathways, leading to enhanced cell invasion. Cumulatively, this study reveals a novel mechanism by which S1P activates parallel pathways that regulate the expression of SNAI2, a master regulator of EMT, and provides new insights into druggable therapeutic targets that may limit cancer metastasis. Wang, W., Hind, T., Lam, B. W. S., Herr, D. R. Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells. FASEB J. 33, 7180–7191 (2019). http://www.fasebj.org

show abstract

Slug is temporally regulated by cyclin E in cell cycle and controls genome stability

Cited by 34 publications

References 30 publications

Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis

Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

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