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A USP28-∆Np63 axis is a druggable vulnerability of squamous tumour formation and maintenance

ABSTRACT: The oncoprotein ∆Np63 is an essential transcriptional master- and cell identity regulator in squamous cell carcinoma (SCC) of various origins, encompassing lung, head and neck, oesophagus, cervix and skin. While in non-transformed cells ∆Np63 protein abundance is tightly regulated by the ubiquitin proteasome system (UPS), in tumours E3-ligases ubiquitylating ∆Np63, such as FBXW7, are commonly mutated or lost, resulting in a hyper-stabilisation of the oncogenic driver. Targeting ∆Np63 protein abundance in SCC could present a possible therapeutic avenue. Here, we report that the deubiquitylase USP28 regulates ∆Np63 protein stability and abundance in SCC by counteracting the degradative UPS system. Interference with USP28 activity by pharmacological inhibition specifically affected human SCC cell lines and, finally, we were able to demonstrate in vivo using CRISPR/Cas9 mouse models that Usp28 is required for SCC induction and maintenance. Hence, targeting USP28 is a viable option to tackle ∆Np63 protein abundance in SCC tumours.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129982 | GEO | 2020/03/04

REPOSITORIES: GEO

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USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.

Project description:Oncogenic transformation of lung epithelial cells is a multi-step process, frequently starting with the inactivation of tumor suppressors and subsequent activating mutations in proto-oncogenes, such as members of the PI3K or MAPK family. Cells undergoing transformation have to adjust to changes, such as metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors, which manifest these adjustments. Here, we report that the deubiquitylase USP28 enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes, such as c-JUN, c-MYC, NOTCH and ∆NP63, at early stages of malignant transformation. USP28 is increased in cancer compared to normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors, such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small molecule inhibitor reset the proteome of transformed cells towards a ‘pre-malignant’ state, and its inhibition cooperated with clinically established compounds used to target EGFRL858R, BRAFV600E or PI3KH1047R driven tumor cells. Targeting USP28 protein abundance already at an early stage via inhibition of its activity therefore is a feasible strategy for the treatment of early stage lung tumours and the observed synergism with current standard of care inhibitors holds the potential for improved targeting of established tumors.

2022-04-08 | PXD032810 | Pride

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer

Project description:SREBP2 controls the expression of enzymes involved in the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol but also provides substrates for protein prenylation, and that is frequently deregulated in cancer. We show here that SREBP2 is a novel substrate for the deubiquitinating enzyme USP28 and that USP28 regulates SREBP2 stability independent of FBXW7. Inhibition of USP28 reduces MVP activity and renders cancer cells highly sensitive to MVP inhibition by statins. Moreover, statin sensitivity of USP28 depleted cells was rescued by the addition of geranyl-geranyl-pyrophosphate, a substrate for protein prenylation. We also provide evidence that SREBP2 participates in the regulation of gene expression signature associated with squamous cell carcinoma (SCC) and that SREBP2 and enzymes of the MVP are overexpressed in SCC from different tissue origins. Finally, deletion of SREBP2 attenuated tumour growth in a mouse model of lung cancer. Our findings suggest that SREBP2 is a novel substrate for USP28 and that combinatorial targeting of the MVP together with USP28 inhibition could be a therapeutic strategy for the treatment of squamous cell carcinomas.

2023-05-16 | GSE204703 | GEO

delta-Np63 loss of function study in the HNSCC cell line UT-SCC-74A

Project description:delta-Np63 is highly expressed in squamous cell carcinoma of the head and neck (HNSCC). To evaluate its function in HNSCC we depleted delta-Np63 by siRNAs in the HNSCC cell line UT-SCC-74A. The transcriptome was analysed by cDNA microarray.

2016-01-14 | E-MTAB-3670 | biostudies-arrayexpress

A USP28-∆Np63 axis is a druggable vulnerability of squamous tumour formation and maintenance

Project description:A USP28-∆Np63 axis is a druggable vulnerability of squamous tumour formation and maintenance

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Effect of Usp28 knockout and re-consitution of wildtype or monomeric Usp28 on gene expression in hepatocellular carcinoma cells

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2023-09-30 | GSE213892 | GEO

∆Np63 executes an oncogenic program through the regulation of a common landscape of super-enhancer associated genes in non-small cell lung cancer

Project description:Distinct lung stem cells give rise to lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ΔNp63 guides development of these cells through regulation of terminal differentiation; however, its mechanistic role in lung cancer development has remained elusive. We utilized a ΔNp63-specific conditional knockout mouse model and found that ∆Np63 maintains lung ADC and SCC by keeping lung stem cells in quiescence. ChIP-seq analysis of lung basal cells and alveolar type 2 (AT2) cells lacking ∆Np63 revealed a robust loss of activating histone marks at super enhancers of cell identity genes defining a unifying oncogenic role for ∆Np63 in non-small cell lung cancer.

2021-12-23 | GSE131671 | GEO

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Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation. RNAseq experiments of E13.5 murine embryonic fibroblasts (MEFs) derived from animals in which Usp28 was either deleted (-/-), wildtype (+/+) or heterozygous (+/-). In a first set of experiments immortalized MEFs of all three genotypes were analysed in biological triplicates. In a second set of experiments immortalized and Ras transformed MEFs of all three genotypes and MEFs which overexpress USP28 (+/+/+) where sequenced in duplicates.

2015-05-01 | E-GEOD-59354 | biostudies-arrayexpress

Dual regulation of Fbw7 function and oncogenic transformation by Usp28

2015-05-01 | GSE59354 | GEO

Effect of ∆Np63 deletion on plasticity of post-injury lung basal cells

Project description:Basal cells were isolated from an influenza-infected non-tamoxifen treated Krt5CreERT2; RFP; ∆Np63flox/flox mouse and cultured, allowing for inducible ∆Np63 deletion in vitro. These basal cells were plated as monolayers, airway organoids, and alveolar organoids and treated with 1uM 4OHT for +4OHT (∆Np63 KO) or equivalent volume DMSO for -4OHT (solvent only, ∆Np63 WT). Technical triplicates of ∆Np63 WT and ∆Np63 KO were harvested for each growth condition for RNA sequencing.

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2014-08-19 | E-GEOD-47417 | biostudies-arrayexpress

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