Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice

Bi, Pengpeng; Feng, Yue; Karki, Anju; Castro, Beatriz; Wirbisky, Sara E.; Wang, Chao; Durkes, Abigail C.; Elzey, Bennett D.; Andrisani, Ourania M.; Bidwell, Christopher A.; Freeman, Jennifer L.; Konieczny, Stephen F.; Kuang, Shihuan

doi:10.1084/jem.20160157

Cited by 85 publications

(92 citation statements)

References 68 publications

(91 reference statements)

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“…We found that the constitutively active form of Notch1 (N1ICD) upregulated Ascl2 in both myoblasts and muscle tissues. Consistently, overexpression of N1ICD also upregulates Ascl2 in adipose tissues (Bi et al, 2016). Our observation is consistent with the report that Rbpj binds to the promoter of Ascl2, and that the N1ICD-Rbpj complex directly activates Ascl2 in skin epidermis (Moriyama et al, 2008).…”

Section: Discussionsupporting

confidence: 92%

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

Wang

Arrington

et al. 2016

Development

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Myogenic regulatory factors (MRFs), including Myf5, MyoD (Myod1) and Myog, are muscle-specific transcription factors that orchestrate myogenesis. Although MRFs are essential for myogenic commitment and differentiation, timely repression of their activity is necessary for the self-renewal and maintenance of muscle stem cells (satellite cells). Here, we define Ascl2 as a novel inhibitor of MRFs. During mouse development, Ascl2 is transiently detected in a subpopulation of Pax7 + MyoD + progenitors (myoblasts) that become Pax7 + MyoD − satellite cells prior to birth, but is not detectable in postnatal satellite cells. Ascl2 knockout in embryonic myoblasts decreases both the number of Pax7 + cells and the proportion of Pax7 + MyoD − cells. Conversely, overexpression of Ascl2 inhibits the proliferation and differentiation of cultured myoblasts and impairs the regeneration of injured muscles. Ascl2 competes with MRFs for binding to E-boxes in the promoters of muscle genes, without activating gene transcription. Ascl2 also forms heterodimers with classical E-proteins to sequester their transcriptional activity on MRF genes. Accordingly, MyoD or Myog expression rescues myogenic differentiation despite Ascl2 overexpression. Ascl2 expression is regulated by Notch signaling, a key governor of satellite cell self-renewal. These data demonstrate that Ascl2 inhibits myogenic differentiation by targeting MRFs and facilitates the generation of postnatal satellite cells.

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Section: Discussionsupporting

confidence: 92%

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

Wang

Arrington

et al. 2016

Development

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“…| 17971 mice (Bi et al, 2014). More interestingly, a recent study demonstrated that activation of Notch induces dedifferentiation of MA and promotes tumorigenic transformation in mice (Bi et al, 2016). Battle et al (2014) demonstrated that obesity-induced leptin-notch signaling in BCa.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide analysis reveals miR‐3184‐5p and miR‐181c‐3p as a critical regulator for adipocytes‐associated breast cancer

Rajarajan

Selvarajan

Raja

et al. 2019

Journal Cellular Physiology

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Obesity is considered as an independent risk factor for breast cancer (BCa) and plays a major role in the breast tumor microenvironment. The etiology and mechanisms by which obesity contributes to BCa development is not yet understood. Herein, we show that in vitro coculture of BCa cells with mature adipocytes (MA‐BCa) increased proliferation, migration, and invasive phenotype of BCa cells. MA‐BCa coculture led to increased production of proinflammatory cytokines and chemokines. To identify microRNAs (miRNAs) in BCa cells that are modulated by the presence of adipocytes, we used small RNA sequencing analysis. Sequencing data revealed that 98 miRNAs were differentially expressed in MA‐BCa. Among them, miR‐3184‐5p and miR‐181c‐3p were found to be the most upregulated and downregulated miRNAs, and direct targets are FOXP4 and PPARα, respectively. In vitro functional assays using a combination of miR‐3184‐5p inhibitor and miR‐181c‐3p mimic synergistically decreased adipocytes‐induced cell proliferation and invasive capacity of BCa cells. Gene Set Enrichment analysis indicated that transcription factors were highly enriched followed by protein kinases, oncogene, and protein regulators in MA‐BCa. GeneGo Metacore pathway analysis uncovered “NOTCH‐induced EMT pathway” was found to be the most abundant in MA‐BCa. Consistently, epithelial–mesenchymal transition‐associated markers were also increased in MA‐BCa. The disease enrichment analysis of the predict target genes revealed that diabetes mellitus was significantly affected disease in MA‐BCa. Taken together, our data suggest that miRNA‐based regulatory mechanism associated with deregulation of pathways and biological functions orchestrated by adipocytes‐secreted factors might drive the BCa progression and metastasis in obese patients.

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“…During 3T3-L1 adipocyte differentiation, significant changes in the lipidome, including specific TAG species and sphingomyelins, have been observed (33). Conversely, de-differentiation of primary, mature adipocytes is associated with changes in the abundance of specific lipid species (4). When taken together, these findings suggest that identification of specific lipidomic signatures could be an alternative approach to assess adipocyte maturity.…”

Section: Knockdown Of 14-3-3z Is Associated With Distinct Changes Inmentioning

confidence: 99%

Reducing 14-3-3ζ expression influences adipocyte maturity and impairs function

Oppong

Diallo

Frayne

et al. 2020

Preprint

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AbstractOne of the primary metabolic functions of a mature adipocyte is to supply energy via lipolysis, or the catabolism of stored lipids. Hormone-sensitive lipase (HSL) is a critical lipolytic enzyme, and its phosphorylation and subsequent activation by PKA generates phospho-binding sites for 14-3-3 proteins, a ubiquitously expressed family of molecular scaffolds. While we previously identified essential roles of the 14-3-3ζ isoform in murine adipogenesis, the presence of 14-3-3 protein binding sites on HSL suggests that 14-3-3ζ could also influence mature adipocyte processes like lipolysis. Herein, we demonstrate that 14-3-3ζ is necessary for lipolysis in male mice and fully differentiated 3T3-L1 adipocytes, as depletion of 14-3-3ζ significantly impaired glycerol and FFA release. Unexpectedly, this was not due to impairments in signaling events underlying lipolysis; instead, reducing 14-3-3ζ expression was found to significantly impact adipocyte maturity, as observed by reduced abundance of PPARγ2 protein and expression of mature adipocytes genes and those associated with de novo triglyceride synthesis and lipolysis. The impact of 14-3-3ζ depletion on adipocyte maturity was further examined with untargeted lipidomics, which revealed that reductions in 14-3-3ζ abundance promoted the acquisition of a lipidomic signature that resembled undifferentiated, pre-adipocytes. Collectively, these findings reveal a novel aspect of 14-3-3ζ in adipocytes, as reducing 14-3-3ζ was found to have a negative effect on adipocyte maturity and adipocyte-specific processes like lipolysis.

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Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice

Cited by 85 publications

References 68 publications

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

Genome‐wide analysis reveals miR‐3184‐5p and miR‐181c‐3p as a critical regulator for adipocytes‐associated breast cancer

Reducing 14-3-3ζ expression influences adipocyte maturity and impairs function

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