USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

Ware, Thomas; Zhu, Hong

doi:10.15252/embr.201847030

Cited by 6 publications

(5 citation statements)

References 15 publications

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“…Leng Lui et al [3]). These findings are in agreement with those presented by Ware and colleagues, where they indicate that, "Our findings agree with the authors reported trend with low USP26 expression conferring to poorer prognosis, although the effect on survival is minor and the clinical relevance remains unclear" [2]. Furthermore, we have now analysed USP26 expression in the most recent TCGA GBM cohort from cBioPortal (TCGA GBM, mRNA RNA-seq v2 RSEM data, z score 2 threshold 1.0, n = 166).…”

Section: Fig 5d In Kitsupporting

confidence: 94%

“…In line with our previous results, we demonstrate that low USP26 expression is associated with poorer overall survival in glioblastoma, at the median threshold (high vs low), showing statistical significance with an overall P-value of 0.0259 (REMBRANDT) (new [3]). These findings are in agreement with those presented by Ware and colleagues, where they indicate that, "Our findings agree with the authors reported trend with low USP26 expression conferring to poorer prognosis, although the effect on survival is minor and the clinical relevance remains unclear" [2]. Furthermore, we have now analysed USP26 expression in the most recent TCGA GBM cohort from cBioPortal (TCGA GBM, mRNA RNA-seq v2 RSEM data, z score 2 threshold 1.0, n = 166).…”

supporting

confidence: 94%

“…

We were recently alerted by Dr. Thomas Ware and Dr. Hong-Jian Zhu that the Kaplan-Meier analysis shown in Figs 5D and EV5B-E of our original study was based on a mixture of glioblastoma, oligodendroglioma and astrocytoma patients [1,2]. Since these tumours are clinically and molecularly distinct, the relevance of USP26 and the tested TGF-b pathway components to the survival of glioblastoma patients was questioned.

…”

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Response to: USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

et al. 2019

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that the Kaplan-Meier analysis shown in Figs 5D and EV5B-E of our original study was based on a mixture of glioblastoma, oligodendroglioma and astrocytoma patients [1,2]. Since these tumours are clinically and molecularly distinct, the relevance of USP26 and the tested TGF-b pathway components to the survival of glioblastoma patients was questioned. Moreover, we were alerted to an error in the statistical analysis in Fig 5A. During the evaluation of the REMBRANDT (REpository for Molecular BRAin Neoplasia DaTa) database (http://www.betastasis.com/ glioma/rembrandt/kaplan_meier_survival_ curve/), we did not realise that the dataset used not only included glioblastoma samples, but also oligodendroglioma and astrocytoma samples. As such, our initial analysis of USP26 expression included all three tumour types and Figs 5D and EV5B-E are thus incorrectly labelled.We have now re-evaluated the expression of USP26 in specifically the REMBRANDT glioblastoma dataset and included further analysis of the TCGA (cBioPortal) glioblastoma datasets. In line with our previous results, we demonstrate that low USP26 expression is associated with poorer overall survival in glioblastoma, at the median threshold (high vs low), showing statistical significance with an overall P-value of 0.0259 (REMBRANDT) (new Fig 5D in Kit Leng Lui et al [3]). These findings are in agreement with those presented by Ware and colleagues, where they indicate that, "Our findings agree with the authors reported trend with low USP26 expression conferring to poorer prognosis, although the effect on survival is minor and the clinical relevance remains unclear" [2]. Furthermore, we have now analysed USP26 expression in the most recent TCGA GBM cohort from cBioPortal (TCGA GBM, mRNA RNA-seq v2 RSEM data, z score 2 threshold 1.0, n = 166). Again, we demonstrate that low USP26 expression correlates with poorer overall survival in glioblastoma patients with a significant P-value of 0.0153 (Fig 1). We have now also included new analyses correlating the expression of USP26 in astrocytoma and oligodendroglioma. We demonstrate that USP26 does not associate with patient survival in oligodendroglioma or astrocytoma (Fig 2A and B). These data are therefore consistent with the conclusions in our original manuscript that loss of USP26 confers poor prognosis in glioblastoma.In a similar fashion, we attempted to correlate TGFBRI, TGFBRII, TGFBRIII, and SMAD7 expression with survival in glioblastoma. As noted, we did not realise that the REMBRANDT dataset was comprised of glioblastoma and lower-grade gliomas. As such, results pertaining to these analyses were also mislabelled. As has been demonstrated in a number of recent publications, high TGF-b activity is a poor prognostic factor in glioblastoma; therefore, we reasoned that deregulated TGFBRI, TGFBRII, TGFBRIII, and SMAD7 expression may also correlate with lower survival outcome. While our new analysis of the REMBRANDT database does not show a correlation between lower patient survival and high TGFBRI, TGFBRII, or TGFBRII...

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Section: Fig 5d In Kitsupporting

confidence: 94%

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confidence: 94%

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“…The journal notes the following issues: Figure 5A reported a statistically significant negative correlation between USP26 and phospho-SMAD2 levels in tissue microarrays from human glioblastoma patients (r = À0.15, P < 0.0001). In response to comments from Thomas MB Ware and Hong-Jian Zhu [2], the authors have provided a re-analysis of their data demonstrating that no significant correlation exists between the expression of these two proteins (r = À0.15, P = 0.18).…”

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USP26 regulates TGF‐β signaling by deubiquitinating and stabilizing SMAD7

Lui¹,

Iyengar²,

Jaynes³

et al. 2019

EMBO Reports

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“…Metastasis is the main cause of cancer-related deaths for breast cancer patients. 1 – 3 Transforming Growth Factor-beta (TGF-β) and its signaling pathway are major drivers of metastasis 3 – 5 and increased TGF-β signaling activity is associated with reduced survival for breast cancer patients. 6 , 7 Accordingly, therapeutics, such as the TGF-β receptor Type I (TβRI) kinase inhibitor SB431542, have been developed to target the TGF-β signaling for treatment of human diseases, including cancer.…”

Section: Introductionmentioning

confidence: 99%

Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

Teixeira,

Wang,

Iaria

et al. 2023

Sig Transduct Target Ther

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Metastasis is the leading cause of cancer-related deaths. Transforming growth factor beta (TGF-β) signaling drives metastasis and is strongly enhanced during cancer progression. Yet, the use of on-target TGF-β signaling inhibitors in the treatment of cancer patients remains unsuccessful, highlighting a gap in the understanding of TGF-β biology that limits the establishment of efficient anti-metastatic therapies. Here, we show that TGF-β signaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle (sEV) secretion. Demonstrating sEV’s unique role, TGF-β signaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β. Further, genetic disruption of sEV secretion in highly-metastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-β signaling to nearly-normal levels. Otherwise, TGF-β signaling activity in non-invasive breast cancer cells is inherently low, but can be amplified by sEVs, enabling invasion and metastasis of poorly-metastatic breast cancer cells. Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers, treatment with dimethyl amiloride (DMA) decreases sEV secretion, TGF-β signaling activity, and breast cancer progression in vivo. Targeting both the sEV trafficking and TGF-β signaling by combining DMA and SB431542 at suboptimal doses potentiated this effect, normalizing the TGF-β signaling in primary tumors to potently reduce circulating tumor cells, metastasis, and tumor self-seeding. Collectively, this study establishes sEVs as critical elements in TGF-β biology, demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-β signaling levels in breast cancer cells.

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USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

Abstract: Comment on “USP26 regulates TGF‐β signaling by deubiquitinating and stabilizing SMAD7” by Kit Leng Lui et al.

Cited by 6 publications

References 15 publications

Response to: USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

Response to: USP26 regulates TGF‐β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma

USP26 regulates TGF‐β signaling by deubiquitinating and stabilizing SMAD7

Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

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