Daxx inhibits muscle differentiation by repressing E2A‐mediated transcription

Gupta, Amitabh; Hou, Rong; Li, Liming; Hiroyasu, Shungo; Hadix, Jennifer A.; Huggins, Gordon S.; Sibinga, Nicholas E.S.

doi:10.1002/jcb.22140

Cited by 7 publications

(6 citation statements)

References 54 publications

(96 reference statements)

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“…Daxx has multiple roles in various biological processes and human diseases, including cancer3738. To study the potential roles of Daxx in lung cancer invasion and/or metastasis, we first investigated endogenous Daxx expression in various lung cancer cell lines.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Furthermore, DAXX can inhibit myogenic differentiation through interactions with the E2A pro-myogenic transcription factor and recruitment of histone deacetylases to E2A-dependent promoters. 58 Therefore, we speculate that DAXX may be recruited to chromocentres during muscle differentiation to mediate the large-scale heterochromatin reorganization events that mark myogenesis, which may explain why the loss of DAXX has such devastating consequences in development. 59 Similarly, mice with skeletal muscle-specific conditional ATRX knock-out show myogenic defects, 60 further implicating DAXX and ATRX in regulation of normal muscle development.…”

Section: Discussionmentioning

confidence: 96%

Myogenic differentiation triggers PML nuclear body loss and DAXX relocalization to chromocentres

et al. 2017

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The promyelocytic leukemia protein (PML) is expressed in most normal human tissues and forms nuclear bodies (NBs) that have roles in gene regulation and cellular processes such as DNA repair, cell cycle control, and cell fate decisions. Using murine C2C12 myoblasts, we demonstrate that activation of skeletal muscle differentiation results in loss of PML and PML NBs prior to myotube fusion. Myotube formation was associated with marked chromatin reorganization and the relocalization of DAXX from PML NBs to chromocentres. MyoD expression was sufficient to cause PML NB loss, and silencing of PML induced DAXX relocalization. Fusion of C2C12 cells using the reptilian reovirus p14 fusogenic protein failed to disrupt PML NBs yet still promoted DAXX redistribution and loss; whereas ectopic expression of PML in differentiated cells only partially restored PML NB formation and DAXX localization at NBs. Finally, we determined that the C-terminal SUMO-interacting motif of DAXX is required for its colocalization with ATRX in heterochromatin domains during myotube formation. These data support a model in which activation of myogenic differentiation results in PML NB loss, chromatin reorganization and DAXX relocalization, and provides a paradigm for understanding the consequence of PML loss in other cellular contexts, such as during cancer development and progression.

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“…We further showed that DAXX inhibited anchorage-independent growth of gastric cancer cells, which became more sensitive to chemotherapies when DAXX was overexpressed. With regard to the role of DAXX in the regulation of stem cell differentiation, we only found two reports in the literature—DAXX inhibits muscle stem cell differentiation by repressing E2A-dependent expression of key myogenic genes via HDAC recruitment to E2A-dependent promoters, 23 as well as DAXX is involved in cell fate conversions through transcriptomic rewiring by regulating the deposition of H3.3 on heterochromatin. 24 Although we do not know how DAXX regulates the expression of CD44 and Oct4, it is likely that DAXX-mediated epigenetic modifications play a role.…”

Section: Discussionmentioning

confidence: 99%

DAXX inhibits cancer stemness and epithelial–mesenchymal transition in gastric cancer

Ding

Wang

et al. 2020

Br J Cancer

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Background DAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown. Methods We analysed the expression of DAXX in 83 pairs of gastric cancer samples, including neoplastic and adjacent tissues, and correlated the expression levels with clinical stages. We also investigated the molecular mechanisms by which DAXX downregulation promotes cancer growth using both in vitro and in vivo models. Results DAXX was downregulated in advanced gastric cancer samples. The expression of DAXX inversely correlates with that of cancer stem cell markers CD44 and Oct4 in gastric cancer lines. DAXX overexpression in gastric cancer cells inhibited migration, invasion and epithelial– mesenchymal transition (EMT). The inhibition of EMT was achieved through the repression of SNAI3, a key inducer of EMT, by recruiting HDAC-1 into the nucleus. Using a xenograft mouse model, we demonstrated that the MKN45 cells formed smaller tumours when DAXX was overexpressed. Wild-type AGS cells were not able to form tumours in nude mice, but in contrast, formed visible tumours when DAXX was silenced in the cells. Conclusion We for the first time demonstrated that DAXX functions as a tumour suppressor in gastric cancer by inhibiting stem cell growth and EMT.

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Daxx inhibits muscle differentiation by repressing E2A‐mediated transcription

Cited by 7 publications

References 54 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

Myogenic differentiation triggers PML nuclear body loss and DAXX relocalization to chromocentres

DAXX inhibits cancer stemness and epithelial–mesenchymal transition in gastric cancer

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