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PXD021738

PXD021738 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleInhibition of CBP synergizes with the RNA-dependent mechanisms of azacitidine by limiting protein translation
DescriptionThe nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.
HostingRepositoryPRIDE
AnnounceDate2021-09-22
AnnouncementXMLSubmission_2021-09-22_07:43:49.457.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJoan Josep Bech-Serra
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-09-29 05:26:04ID requested
12021-09-22 07:43:49announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: myelodysplastic syndromes
secondary acute myeloid leukemia, clonal hematopoietic disorders, hypomethylating agents
azacitidine
epigenetic regulation
lysine acetyl tranferase inhibitors
CREB binding protein / CBP / p300
shRNA screen
protein synthesis
Contact List
Marcus Buschbeck
contact affiliation1)Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), 08916 Badalona, Spain 2)Cancer and Leukemia Epigenetics and Biology Program, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-GTP-UAB, 08916 Badalona, Spain
contact emailmbuschbeck@carrerasresearch.org
lab head
Joan Josep Bech-Serra
contact affiliationProteomics Unit - Josep Carreras Leukaemia Research Institute
contact emailjbech@carrerasresearch.org
dataset submitter
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Dataset FTP location
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