Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers

MacFawn, Ian P.; Wilson, Hannah; Selth, Luke A.; Leighton, Ian; Serebriiskii, Ilya G.; Bleackley, R. Chris; Elzamzamy, Osama M; Farris, Joshua C.; Pifer, Phillip M.; Richer, Jennifer K.; Frisch, Steven M.

doi:10.1016/j.molimm.2018.11.006

Cited by 23 publications

(16 citation statements)

References 89 publications

(152 reference statements)

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“…To build on previous studies, in which EMT induced a consistent upregulation of NKG2D ligand expression in colorectal carcinoma cell lines, we performed this detection of EMT in CTCs. Recently, several studies also showed mesenchymal features in lung or breast cancer models was correlated with resistance to NK cells or cytotoxic T lymphocytes attacks . However, to the best of our knowledge, this is the first study to evaluate the relationship between EMT and ULBP1 expression in gastric CTCs.…”

Section: Discussionmentioning

confidence: 86%

Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

Tian

et al. 2020

Cancer Medicine

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Background:Increasing numbers of studies have demonstrated that circulating tumor cells (CTCs) undergo a phenotypic change termed epithelial-mesenchymal transition (EMT), and researchers have proposed that EMT might provide CTCs with increased potential to survive in the different microenvironments encountered during metastasis through various ways, such as by increasing cell survival and early colonization. However, the exact role of EMT in CTCs remains unclear. Methods: In this study, we identified CTCs of 41 patients with gastric cancer using Cyttel-CTC and im-FISH (immune-fluorescence in situ hybridization) methods, and tested the expression of EMT markers and ULBP1 (a major member of the NKG2Dnatural killer [NK] group 2 member D-ligand family) on CTCs. Moreover, we investigated the relationship between the expression of EMT markers and ULBP1 on CTCs and gastric cancer cell lines. Results: Our results showed that the CTCs of gastric cancer patients exhibited three EMT marker subtypes, and that the expression of ULBP1 was significantly lower on mesenchymal phenotypic CTCs (M + CTCs) than on epithelial phenotypic CTCs (E + CTCs). EMT induced by TGF-β in vitro produced a similar phenomenon, and we therefore proposed that EMT might be involved in the immune evasion of CTCs from NK cells by altering the expression of ULBP1. Conclusions: Our study indicated that EMT might play a vital role in the immune invasion of CTCs by regulating the expression of ULBP1 on CTCs. These findings could provide potential strategies for targeting the immune evasion capacity of CTCs.

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Section: Discussionmentioning

confidence: 86%

Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

Tian

et al. 2020

Cancer Medicine

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“…In addition to being thought of as PSFs, GRHL2 and OVOL1/2 have been considered as METinducing transcription factors (MET-TFs) as their overexpression in carcinomas is capable of upregulating the expression levels of E-cadherin and/or revert EMT [50][51][52][53][54] as well as other EMT-associated traits such as anoikis-resistance, metabolic reprogramming [55] and immune evasion [56]. This observation is consistent with their knockdown known to drive a 'full' EMT in both cancer cell lines and in developmental contexts [46,49].…”

Section: The Effect Of Phenotypic Stability Factors (Psfs) On the Phementioning

confidence: 99%

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Pasani

Sahoo

Jolly

2020

Preprint

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Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are a) their ability to dynamically move along the epithelial-hybrid-mesenchymal spectrum and b) their tumor-initiation potential or stemness. With increasing functional characterization of hybrid epithelial /mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parameter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to 'pure' epithelial or mesenchymal states. We also integrate multiple 'phenotypic stability factors' (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro - such as OVOL1/2, GRHL2, and NRF2 - with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) being essential for tumor-initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT and stemness networks.

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“…A conserved alphahelix between residues 425437 of GRHL2 has previously been shown to inhibit P300 [44] . We therefore overexpressed GRHL2 Δ425437, a previously demonstrated nonp300inhibitory mutant [44], [45] , in three ER positive breast cancer cell lines (MCF7, T47D…”

Section: Grhl2 Constrains Er Binding and Activitymentioning

confidence: 99%

“…RNAseq breast cancer data was downloaded from TCGA on January 2015 and VSTNormalized as described by Anders and Huber [57] . The ARACNe transcriptional regulation network was imported into R using the VIPER BioConductor package and it was interrogated using the differential binding profiles from our ChIPseq experiment as signatures, 45 22 qPLEXRIME Samples were prepared as previously described for RIME [9] , protocol was modified to include TMT isobaric labels for quantification [34] . qPLEXRIME data and analysis pipeline is available as part of the supplementary Rmarkdown.…”

Section: Motif Analysismentioning

confidence: 99%

Network analysis of ChIP-seq data by VULCAN identifies GRHL2 as a key co-regulator of ERa in luminal breast cancer

Giorgi

Donnelly

et al. 2018

Preprint

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Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers

Cited by 23 publications

References 89 publications

Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Network analysis of ChIP-seq data by VULCAN identifies GRHL2 as a key co-regulator of ERa in luminal breast cancer

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