LUBAC determines chemotherapy resistance in squamous cell lung cancer

Ruiz, E Josue; Diefenbacher, Markus E.; Nelson, Jessica K.; Sancho, Rocı́o; Pucci, Fabio; Chakraborty, Atanu; Moreno, Paula; Annibaldi, Alessandro; Liccardi, Gianmaria; Encheva, Vesela; Mitter, Richard; Rosenfeldt, Mathias T.; Snijders, Ambrosius P.; Meier, Pascal; Calzado, Marco A.; Behrens, Axel

doi:10.1084/jem.20180742

Cited by 66 publications

(80 citation statements)

References 52 publications

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“…∆Np63 is tightly regulated by the ubiquitin–proteasome system and ubiquitylated by various E3 ligases (Armstrong et al , ). In a tumour, this mechanism is frequently non‐functional, leading to the accumulation of ∆Np63 protein (Ruiz et al , ) and results of the current study.…”

Section: Discussionmentioning

confidence: 49%

“…∆Np63 is an unstable protein that is continuously turned over by the proteasome upon ubiquitination by E3 ligases, such as the FBXW7 ubiquitin ligase (Galli et al , ). FBXW7 is frequently mutated or deleted in SCC tumours (cervix 13.15%, HNSC 7.55%, lung 6.4% and oesophagus 7.29%; cBioPortal, Galli et al , ; Ruiz et al , ). Intriguingly, it has been shown previously that the degradation of many targets of FBXW7 is counteracted by the deubiquitylase (DUB) USP28 (Popov et al , 2007b).…”

Section: Introductionmentioning

confidence: 99%

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Maintaining protein stability of ∆Np63 via USP 28 is required by squamous cancer cells

et al. 2020

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The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.

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Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Maintaining protein stability of ∆Np63 via USP 28 is required by squamous cancer cells

et al. 2020

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“…Previous studies have shown that SCC tumors exhibited limited response rates to therapy and consequently poorer prognosis than ADC in overall survival (Prieto-Garcia et al, 2020a;Ruiz et al, 2019). In lung SCC, the expression of DDR signature genes was elevated when compared to normal tissue or ADC ( Figure S3A).…”

Section: Loss Of Usp28 Negatively Affects the Expression Of Ddr Effecmentioning

confidence: 87%

Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway

Prieto-Garcia¹,

Hartmann²,

Reissland³

et al. 2020

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Squamous cell carcinomas (SCC) frequently have a limited response to or develop resistance to platinum-based chemotherapy, and have an exceptionally high tumor mutational burden. As a consequence, overall survival is limited and novel therapeutic strategies are urgently required, especially in light of a rising incidences. SCC tumors express ΔNp63, a potent regulator of the Fanconi Anemia (FA) DNA-damage response pathway during chemotherapy, thereby directly contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 affects the FA DNA repair pathway during cisplatin treatment in SCC, thereby influencing therapy outcome. In an ATR-dependent fashion, USP28 is phosphorylated and activated to positively regulate the DNA damage response. Inhibition of USP28 reduces recombinational repair via an ΔNp63-Fanconi Anemia pathway axis, and weakens the ability of tumor cells to accurately repair DNA. Our study presents a novel mechanism by which tumor cells, and in particular ΔNp63 expressing SCC, can be targeted to overcome chemotherapy resistance.SignificanceLimited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ΔNp63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-ΔNp63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.

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“…We used GSE6410 (6 samples mRNAs ) and GSE43249 (6 samples miRNAs ) [20] about cisplatin resistant nonsmall cell lung cancer (NSCLC) cells from the GEO database (https://www.ncbi.nlm.nih.gov/gds/?term=). First, DEmRNAs were analyzed by online software GEO2R.…”

Section: Data Collection and Microarray Analysismentioning

confidence: 99%

LncRNA XIST acts as a microRNA-520 sponge to regulate the cisplatin resistance in NSCLC cells by mediating BAX through ceRNA network

Liu

et al. 2020

Preprint

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Background In recent years, LncRNA acts as a member of competing endogenous RNA (ceRNA), playing an important role in drug resistance of lung cancer. The aim of this study was to identify potential biomarkers about cisplatin resistant lung cancer cells using a comprehensive ceRNA network. Methods GSE6410 (GPL-201) analyzed gene expression changes about cispaltin resistance in A549 NSCLC cells. GSE43249 (GPL-14613) included noncoding RNA expression profiling derived from the cisplatin resistant A549 lung cells. GEO2R, an online analysis tool, analyzed the differentially expressed mRNAs and miRNAs (DEmRNAs and DEmiRNAs). To explore the functional enrichment implication of differentially expressed mRNAs, we used the GO and KEGG pathway analysis. Through miRDB、Targetscan、Starbase、miRWalk, we found targeted miRNAs. The Kaplan-Meier curve method was used to show clinical survival analysis of targeted RNAs (P < 0.05). The Starbase database predicted potential lncRNAs mediated targeted miRNAs. Eventually, the novel ceRNA network of lncRNAs, miRNAs, mRNA was constructed by cytoscape3.7.2. Results 118 differentially expressed mRNAs were the basis of the mediated ceRNA network. DAVID and Kaplan-Meier picked out BAX, an apoptosis regulator. Venn Diagram demonstrated 8 miRNAs commomly regulating Bax. Starbase predicted lncRNA XIST mediated miRNAs. Finally, lncRNA XIST maybe a useful biomarker regulating cisplatin resistance in lung cancer cells. Conclusions LncRNA XIST competitively bound to miRNA 520 in the regulation of cisplatin resistance by BAX, participating apoptosis in the p53 signaling pathway.

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LUBAC determines chemotherapy resistance in squamous cell lung cancer

Abstract: This study identifies a novel therapeutic strategy against cisplatin-resistant lung squamous cell carcinoma (LSCC) using mouse models and patient samples. LSCC chemoresistance depends on LUBAC and high NF-κB activity, mechanisms that can be targeted to increase therapy response.

Cited by 66 publications

References 52 publications

Maintaining protein stability of ∆Np63 via USP 28 is required by squamous cancer cells

Maintaining protein stability of ∆Np63 via USP 28 is required by squamous cancer cells

Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway

LncRNA XIST acts as a microRNA-520 sponge to regulate the cisplatin resistance in NSCLC cells by mediating BAX through ceRNA network

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