Tissue transglutaminase activates integrin-linked kinase and β-catenin in ovarian cancer

Condello, Salvatore; Prasad, Mayuri; Atwani, Rula; Matei, Daniela

doi:10.1016/j.jbc.2022.102242

Cited by 15 publications

(16 citation statements)

References 63 publications

(95 reference statements)

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“…The secretion of TG2 from cells to the ECM has been implicated in outside-in signalling in several cancer models [ 16 , 22 , 34 ], and recently TG2 has been proposed to be externalised via microvesicles/extracellular vesicles (EVs) in cancer [ 35 – 37 ] and other systems [ 38 – 40 ]. The presence of extracellular TG2 in EVs isolated from PC3 serum-free conditioned medium (CM), was demonstrated by density gradient, which showed TG2 in the EVs-rich fraction 4 where all the tested EVs markers were also concentrated (ALIX, CD63 and FLOT-2) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Canonical and truncated transglutaminase-2 regulate mucin-1 expression and androgen independency in prostate cancer cell lines

et al. 2023

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Androgen independency is associated with poor prostate cancer (PCa) survival. Here we report that silencing of transglutaminase-2 (TG2) expression by CRISPR-Cas9 is associated with upregulation of androgen receptor (AR) transcription in PCa cell lines. Knockout of TG2 reversed the migratory potential and anchorage independency of PC3 and DU145 cells and revealed a reduced level of mucin-1 (MUC1) RNA transcript through unbiased multi-omics profiling, which was restored by selective add-back of the truncated TG2 isoform (TGM2_v2). Silencing of AR resulted into increased MUC1 in TG2KO PC3 cells showing that TG2 affects transcriptional regulation of MUC1 via repressing AR expression. Treatment of PC3 WT cell line with TG2 inhibitor ZDON led to a significant increase in AR expression and decrease in MUC1. ZDON also blocked the formation of MUC1-multimers labelled with TG amine-donor substrates in reducing conditions, revealing for the first time a role for TG2, which we show to be externalised via extracellular vesicles, in MUC1 stabilisation via calcium-dependent transamidation. A specific antibody towards TGM2_v2 revealed its restricted nuclear location compared to the canonical long form of TG2 (TGM2_v1), which is predominantly cytosolic, suggesting that this form contributes to the previously suggested TG2-mediated NF-κB activation and AR transcriptional repression. As TGM2_v2 transcription was increased in biopsies of early-stage prostate adenocarcinoma (PRAD) patients compared to subjects presenting inflammatory prostatitis, and total TG2 protein expression significantly increased in PRAD versus normal tissue, the role of TG2 and its truncated form as a prostate malignancy marker is suggested. In conclusion, this investigation has provided the first unbiased discovery of a novel pathway mediated by TG2 via MUC1, which is shown to contribute to androgen insensitivity and malignancy of PCa cells and be upregulated in PCa biopsies, with potential relevance to cancer immune evasion.

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Section: Resultsmentioning

confidence: 99%

Canonical and truncated transglutaminase-2 regulate mucin-1 expression and androgen independency in prostate cancer cell lines

et al. 2023

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“…GPR56 signaling has been shown to modulate the Wnt pathway in GBM and adipogenesis (Al Hasan et al 2020; Shashidhar et al 2005). Besides that, TG2 also plays an important role in the stabilization and nuclear translocation of β‐catenin by binding to LRP5/6, inducing the TCF /LEF transcription factors, and decreasing CDKN1A expression (Condello et al 2022). TG2 inhibition has also been shown to suppress Wnt signaling by reducing β‐catenin levels (Han et al 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, TG2/Fibronectin integrin complex formation on the surface of cancer cell membranes was shown to regulate β‐catenin expression and loss of TG2 also decreased mesenchymal markers like MMP‐2, TWIST‐, CD44, etc. (Condello et al 2022; Sima et al 2022), thus implying a cross‐talk between GPR56—TG2 dynamics and integrin signaling associated with the cytoskeletal reorganization and cell invasion.…”

Section: Resultsmentioning

confidence: 99%

GPR56 signaling pathway network and its dynamics in the mesenchymal transition of glioblastoma

Ganesh,

Venkataraman,

Sirdeshmukh

2023

J. Cell Commun. Signal.

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G protein-coupled receptor 56 (GPR56/ADGRG1) is a multifunctional adhesion GPCR involved in diverse biological processes ranging from development to cancer. In our earlier study, we reported that GPR56 is expressed heterogeneously in glioblastoma (GBM) and is involved in the mesenchymal transition, making it a promising therapeutic target (Ganesh et al., 2022). Despite its important role in cancer, its mechanism of action or signaling is not completely understood. Thus, based on transcriptomic, proteomic, and phosphoproteomic differential expression data of GPR56 knockdown U373-GBM cells included in our above study along with detailed literature mining of the molecular events plausibly associated with GPR56 activity, we have constructed a signaling pathway map of GPR56 as may be applicable in mesenchymal transition in GBM. The map incorporates more than 100 molecular entities including kinases, receptors, ion channels, and others associated with Wnt, integrin, calcium signaling, growth factors, and inflammation signaling pathways. We also considered intracellular and extracellular factors that may influence the activity of the pathway entities. Here we present a curated signaling map of GPR56 in the context of GBM and discuss the relevance and plausible cross-connectivity across different axes attributable to GPR56 function.

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“…The secretion of TG2 from cells to the ECM has been implicated in outside-in signalling in several cancer models [16,22,34], and recently TG2 has been proposed to be externalised via microvesicles/extracellular vesicles (EVs) in cancer [35,36] and other systems [37][38][39]. The presence of extracellular TG2 in EVs isolated from PC3 serum-free conditioned medium (CM), was demonstrated by density gradient, which showed TG2 in the EVs-rich fraction 4 where all the tested EVs markers were also concentrated (ALIX, CD63 and FLOT-2) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transglutaminase-2 regulates mucin-1 expression and androgen independency in prostate cancer cell lines via an alternative truncated isoform

Atobatele

Tonoli

Vadakekolathu

et al. 2022

Preprint

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Androgen independency is associated with poor prostate cancer (PCa) survival. Here we report that silencing of transglutaminase-2 (TG2) expression by CRISPR-Cas9 is associated with upregulation of androgen receptor (AR) transcription in prostate cancer cell lines. Knockout of TG2 reversed the migratory potential and anchorage independency of PC3 and DU145 cells and revealed a reduced level of MUC1 RNA transcript through unbiased multi-omics profiling, which was restored by selective add back of the truncated TG2 isoform (TGM2_v2). Silencing of AR resulted into increased MUC1 in TG2KO PC3 cells showing that TG2 affects transcriptional regulation of MUC1 via repressing AR expression. Treatment of PC3 WT cell line with TG2 inhibitor ZDON led to a significant increase in AR expression and decrease in MUC1. ZDON also blocked the formation of MUC1-multimers labelled with TG amine-donor substrates in reducing conditions, revealing for the first time a role for TG2, which we show to be externalised via extracellular vesicles, in MUC1 stabilisation via calcium-dependent transamidation. A specific antibody towards TGM2_v2 revealed its restricted nuclear location compared to the canonical long form of TG2 (TGM2_v1), which is predominantly cytosolic, suggesting that this form contributes to the previously suggested TG2-mediated NF-κB activation and AR transcriptional repression. As TGM2_v2 transcription was increased in biopsies of early-stage prostate cancer patients compared to subjects presenting inflammatory prostatitis, the role of TG2 truncated form as a prostate malignancy marker is suggested. In conclusion, this investigation has provided the first unbiased discovery of a novel pathway mediated by an aberrant form of TG2 via MUC1, which is shown to contribute to androgen insensitivity and malignancy of PCa cells and be upregulated in prostate cancer biopsies, with potential relevance to cancer immune evasion.

show abstract

Tissue transglutaminase activates integrin-linked kinase and β-catenin in ovarian cancer

Cited by 15 publications

References 63 publications

Canonical and truncated transglutaminase-2 regulate mucin-1 expression and androgen independency in prostate cancer cell lines

Canonical and truncated transglutaminase-2 regulate mucin-1 expression and androgen independency in prostate cancer cell lines

GPR56 signaling pathway network and its dynamics in the mesenchymal transition of glioblastoma

Transglutaminase-2 regulates mucin-1 expression and androgen independency in prostate cancer cell lines via an alternative truncated isoform

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