PXD021738-1

PXD021738 is an original dataset announced via ProteomeXchange.

Title	Inhibition of CBP synergizes with the RNA-dependent mechanisms of azacitidine by limiting protein translation
Description	The 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.
HostingRepository	PRIDE
AnnounceDate	2021-09-22
AnnouncementXML	Submission_2021-09-22_07:43:49.457.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joan Josep Bech-Serra
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-29 05:26:04	ID requested
⏵ 1	2021-09-22 07:43:49	announced

Dataset with its publication pending

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

Marcus Buschbeck
contact affiliation	1)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 email	mbuschbeck@carrerasresearch.org
lab head
Joan Josep Bech-Serra
contact affiliation	Proteomics Unit - Josep Carreras Leukaemia Research Institute
contact email	jbech@carrerasresearch.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/09/PXD021738

PRIDE project URI

• PRIDE
  1. PXD021738
     1. Label: PRIDE project
     2. Name: Inhibition of CBP synergizes with the RNA-dependent mechanisms of azacitidine by limiting protein translation