ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

Bolado-Carrancio, Alfonso; Muir, Morwenna; Ewing, Ailith; MacLeod, Kenneth G.; Nguyen, Lan K.; Carragher, Neil O.; Semple, Colin A.; Brunton, Valerie G.; Caswell, Patrick T.; Kriegsheim, Alex von

doi:10.1101/767533

Cited by 2 publications

(4 citation statements)

References 59 publications

(65 reference statements)

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“…In our experimental conditions, ISG15 gene silencing inhibited proliferation, but not migration or invasion; in contrast with other published work that observed a decrease of either of these tumoral characteristics in different malignancies [22,23,25,40,41]. However, this might indicate that ISG15 pro-tumoral functions are heterogeneous and depend on the cancer type.…”

Section: Discussioncontrasting

confidence: 99%

“…ISG15 oncogenic mechanisms are also diverse, as it can act intracellularly in its free [27,28] or its conjugated form [22,25,44]; as well as extracellularly as a microenvironmental modulator [23,28,30]. More specifically, both paracrine secretion from M2 macrophages and autocrine ISG15 secretion from pancreatic tumour cells are able to induce a CSC phenotype in said cells [28,30].…”

Section: Discussionmentioning

confidence: 99%

“…Following viral infection, type-I interferons (IFNα/β) are known to induce ISG15 expression and its conjugation with target proteins [12]. Recent studies have focused on the role of ISG15 in other major cellular processes, such as DNA repair [13][14][15], autophagy [16,17] or protein translation, as well as in pathological contexts like genotoxic stress or tumour development [18][19][20][21][22][23][24][25]. In sarcoma patients, ISG15 expression is up-regulated in tumour tissue compared to normal tissue, and its expression was included in a metastasis-related genetic signature for poor prognosis [26].…”

Section: Introductionmentioning

confidence: 99%

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ISG15 as a prognostic biomarker in solitary fibrous tumour

Mondaza-Hernandez

Moura

López-Álvarez

et al. 2022

Cell. Mol. Life Sci.

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Background Solitary fibrous tumour (SFT) is a rare mesenchymal malignancy that lacks robust prognostic and predictive biomarkers. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier, associated with tumour progression, and with poor survival of SFT patients, as previous published by our group. Here, we describe the role of ISG15 in the biology of this rare tumour. Methods ISG15 expression was assessed by immunohistochemistry in tissue microarrays from SFT patients and tested for correlation with progression-free survival and overall survival (OS). The effects of ISG15 knockdown or induction were investigated for cancer stem cell (CSC) characteristics and for drug sensitivity in unique in vitro models of SFT. Results The prognostic value of ISG15 for OS was validated at protein level in malignant SFT patients, prospectively treated with pazopanib and enrolled in GEIS-32 trial. In SFT in vitro models, ISG15 knockdown lead to a decrease in the expression of CSC-related genes, including SOX2, NANOG, ALDH1A1, ABCB1 and ABCC1. Likewise, ISG15 downregulation decreased the clonogenic/ tumoursphere-forming ability of SFT cells, while enhancing apoptotic cell death after doxorubicin, pazopanib or trabectedin treatment in 3D cell cultures. The regulation of CSC-related genes by ISG15 was confirmed after inducing its expression with interferon-β1; ISG15 induction upregulated 1.28- to 451-fold the expression of CSC-associated genes. Conclusions ISG15 is a prognostic factor in malignant SFT, regulating the expression of CSC-related genes and CSCs maintenance. Our results suggest that ISG15 could be a novel therapeutic target in SFT, which could improve the efficacy of the currently available treatments.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ISG15 as a prognostic biomarker in solitary fibrous tumour

Mondaza-Hernandez

Moura

López-Álvarez

et al. 2022

Cell. Mol. Life Sci.

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“…It has been reported that GOLM1 selectively interacts with EGFR and assists EGFR recycling back to the plasma membrane to drive hepatocellular carcinoma metastasis [35]. EGFR recycling is also regulated by ISGylation leading to the more aggressive tumor behaviors observed in breast cancer [47]. Besides these regulations, several ubiquitin ligases were also reported to be involved in EGFR trafficking and recycling such as CHIP and SMURF2 [48,49].…”

Section: Discussionmentioning

confidence: 99%

PELI1 and EGFR cooperate to promote breast cancer metastasis

et al. 2023

Oncogenesis

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Pellino-1 (PELI1) is an E3 ubiquitin ligase acting as a key regulator for the inflammation and autoimmunity via the ubiquitination of the substrate proteins. There is increasing evidence to support that PELI1 functions as an oncoprotein in tumorigenesis and metastasis. However, the molecular mechanism underlying the high expression and oncogenic roles of PELI1 in cancers remains limited. Herein, we revealed a novel regulation mechanism by which PELI1 and EGFR cooperate to promote breast cancer metastasis. EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. The co-inhibition of the PELI1-EGFR showed synergetic effect to repress breast cancer metastasis. Furthermore, we identified a compound S62 as a small molecule disruptor of PELI1/EGFR that effectively repressed breast cancer metastasis. Our study not only uncovered the emerging roles of PELI1/EGFR interaction in the progression of breast cancer, but also provided an effective strategy for the inhibition of metastasis in breast cancer.

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ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

Cited by 2 publications

References 59 publications

ISG15 as a prognostic biomarker in solitary fibrous tumour

ISG15 as a prognostic biomarker in solitary fibrous tumour

PELI1 and EGFR cooperate to promote breast cancer metastasis

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