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USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a therapeutic target in pancreatic cancer

ABSTRACT: Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we developed a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identified USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition resulted in potent growth impairment in PDAC organoids, while normal pancreatic organoids were insensitive, and caused dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinated and stabilised the HIF-1a transcription factor. PDAC is characterised by a severely hypoxic microenvironment, and USP25 depletion abrogated HIF-1a transcriptional activity and impaired glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1a axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.

ORGANISM(S): Mus musculus

PROVIDER: GSE166077 | GEO | 2022/03/01

REPOSITORIES: GEO

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USP25 is a HIF-1 regulator and a therapeutic target in pancreatic ductal adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with both an extremely poor prognosis and response to conventional chemotherapy. Identifying novel biological vulnerabilities is therefore critical in the development of more effective therapies. By using patient-derived organoids and murine genetic models, we developed a pipeline for identifying biologically active deubiquitylases (DUBs) with activity-based proteomics, coupled with a loss-of-function genetic screen in organoids. We found that ubiquitin specific protease 25 (USP25) is indispensable for PDAC progression. Compared with normal pancreatic tissue, USP25 was highly expressed and active in murine PDAC tumours and in primary human PDAC samples. Silencing of Usp25/USP25 led to reduced tumour organoid formation and viability, and transcriptional profiling revealed that USP25 is a regulator of hypoxia, glycolysis and HIF-1 signalling pathways. Mechanistically, we found that USP25 directly interacts with HIF-1 and that its deubiquitylase activity regulates HIF-1 protein stability, nuclear translocation and transcriptional activity. Moreover, treatment with a novel USP25 inhibitor resulted in a dramatic loss of murine and patient-derived organoid viability, HIF-1 signalling, and consequently induced substantial regression of murine and human organoid-derived xenografts in vivo. Thus, USP25 is a promising therapeutic target for the treatment of human PDAC.

2022-05-19 | PXD023424 | Pride

ChIP-seq analysis of HIF-1a and HIF-2a binding in hypoxic cancer cell lines

Project description:Pan-genomic analysis of hypoxic HIF-1a and HIF-2a binding by ChIP-seq in cancer cell lines

2022-11-15 | GSE200203 | GEO

mTORC inhibition of neuroblastoma SK-N-BE(2)c cells cultured under hypoxic conditions

Project description:Differential expression of the oxygen sensitive hypoxia-inducible transcription factor (HIF) subunits HIF-1a and HIF-2a occurs in many tumor types, but the underlying regulatory mechanisms remain poorly understood. Here we investigate the role of mTOR complex in the regulation of HIF expression in cells cultured under hypoxic conditions.

2016-01-01 | GSE69833 | GEO

Transcription profiling of mouse wild type and HIF-1a null hepatocyte cultures under short-term hypoxic conditions vs controls

Project description:The primary aim of this study was to evaluate the changes in hepatocyte gene expression under short-term hypoxic conditions in wild type and HIF-1a null cultures. To this end, hypoxia treated cultures were subjected to incubation with 1% O2/5% CO2/94% N2 at 37Â° C for eight hours prior to RNA isolation. Duplicate normoxic controls were established from separate animals wherein cultures were untreated and treated with Adbgal. Biological triplicates of wild type and HIF-1a null cultures were placed under hypoxic conditions and subsequently processed for microarray analysis. A total of 10 microarray hybridizations were performed.

2007-09-29 | E-GEOD-1321 | biostudies-arrayexpress

USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

Project description:Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. Deubiquitinating enzymes (DUBs) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation.This study set out to investigate the role of a DUB, USP25, in pathological cardiac hypertrophy, reveal its molecular mechanism, and hopefully provide a new therapeutic target for heart failure.We revealed increased protein level of USP25 expression in the cardiomyocytes in response to Ang II stimulation. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and TAC treatment. Mechanistically, LC-MS/MS analysis combined with Co-IP was used to identify SERCA2a, an anti-hypertrophy protein, as an interacting protein of USP25. Also, our data showed that USP25 bound to SERCA2a directly via its USP domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium content in cardiomyocytes. Moreover, restoration of USP25 expression via with AAV9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas SERCA2a myocardial overexpression could offset the effect of USP25.

2023-03-01 | GSE221396 | GEO

Secretome analysis of Pancreatic Cancer Spheroid with myeloid cell infiltration

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most hypoxic, lethal, and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with the abundance of myeloid cell infiltration and scare T cell infiltration, PDAC is considered a cold tumor. Using MiaPaCA-2 as a PDAC spheroid model with hypoxic core grown in serum-free defined media and immune cell infiltration, we assessed the modulation of PDAC secretome and characterized immunomodulatory factors secreted.

2023-12-15 | PXD044177 | Pride

Gene Expression profiles of colon from Hif-1α+/+, Hif-1αLSL/LSL

Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-1α in colon, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-1α+/+, Hif-1αLSL/LSL mice. Background & Aims: The progression and growth of solid tumors leads to a state where tumors outgrow their capacity for efficient oxygenation and nutrient uptake and an increase in tumor hypoxia. Tumor hypoxic response is mediated by hypoxia-inducible factor (HIF)-1a and HIF-2a. These transcription factors regulate a battery of genes that are critical for tumor oxygenation, tumor metabolism, and cell proliferation and survival. Therefore, inhibitors of HIF have been sought for as anti-neoplastic agents in several different kinds of cancers. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1a is beneficial, and can reduce intestinal inflammation. The efficacy of pharmacological agents that chronically activate HIF-1a are decreased due to the tumorigenic potential of HIF. However, recent advance in understanding HIF signaling have identified mechanisms, which could allow for isoform specific activators. Activation of HIF-2a increases colon carcinogenesis and progression in mouse models. However, the role of chronic HIF-1a activation is unclear in the progression in colon cancer. The present data demonstrates that activation of HIF-1a in epithelial cells does not increase colon carcinogens or progression in two mouse models of colon cancer, and provides the proof of principle that HIF-1a activation maybe safe as therapies for inflammatory bowel disease. Global gene expression profiling in colon RNAs isolated from 6- to 8-week-old Hif-1α+/+ (n=5, Shah 019) and Hif-1αLSL/LSL (n=5, Shah 020).

2014-05-14 | E-GEOD-55915 | biostudies-arrayexpress

Hypoxic response in wild type and HIF-1alpha null hepatoctyes

Project description:The primary aim of this study was to evaluate the changes in hepatocyte gene expression under short-term hypoxic conditions in wild type and HIF-1a null cultures. To this end, hypoxia treated cultures were subjected to incubation with 1% O2/5% CO2/94% N2 at 37° C for eight hours prior to RNA isolation. Duplicate normoxic controls were established from separate animals wherein cultures were untreated and treated with Adbgal. Biological triplicates of wild type and HIF-1a null cultures were placed under hypoxic conditions and subsequently processed for microarray analysis. A total of 10 microarray hybridizations were performed. Keywords: repeat sample

2006-01-28 | GSE1321 | GEO

Transcription profiling by array of human pacreatic islets prepared for clinical transplantation

Project description:This study compared 9 human islet preparations, extracted and prepared for clinical transplantation. Human islets were isolated as, and all were of transplant quality. Unamplified RNA was extracted and hybridized to Affymetrix HGU133+2 arrays. By using gene set enrichment analysis to investigate the variability of each probeset on the array, it was clear that isolated human islets undergo varying degrees of hypoxic stress. Further to this, key glycolytic genes, all of which are under the control of hypoxia inducing factor 1a (HIF-1a) were activated, indicating a switch towards anareobic glycolysis. Glycolysis severely impairs the ability of islets to sense glucose and secrete insulin in response to elevated blood sugar. We confirmed these findings in mouse rodents, demonstrated a dependance upon HIF-1a, and showed that even after 4 weeks, hypoxic islets retained their glycolytic molecular profile.

2011-02-26 | E-MTAB-203 | biostudies-arrayexpress

mTORC inhibition of neuroblastoma SK-N-BE(2)c cells cultured under hypoxic conditions

2016-07-03 | E-GEOD-69833 | biostudies-arrayexpress

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