PXD033891

PXD033891 is an original dataset announced via ProteomeXchange.

Title	Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer
Description	Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer deaths in men. GWAS studies have identified variants associated with prostate cancer susceptibility, however, mechanistic and functional validation of these mutations are lacking. Mitochondrial energy metabolism plays an important role in the onset and development of cancer. A missense variant was identified in the ELAC2 gene, which encodes a dually localized nuclear and mitochondrial RNA processing enzyme, with predicted impact on metabolism and tumorigenesis. We used CRISPR/Cas9 genome editing to introduce this variant into the mouse Elac2 gene as well as to generate a prostate-specific gene knockout of Elac2. The mutations caused enlargement and inflammation in the prostate and nodule formation. Multi-omic profiling revealed defects in RNA and energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired processing of mitochondrial and nuclear encoded non-coding RNAs and reduced protein synthesis. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer and led to metastasis. Our systems biology analyses reveal a miRNA-mediated molecular mechanism by which specific non-coding RNAs elicit metabolic changes that drive prostate tumorigenesis and metastasis. We conclude that the ELAC2 variant is a predisposing factor for prostate cancer and provide a detailed molecular mechanism and physiologically relevant models of this cancer.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:56:51.197.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Timothy McCubbin
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-13 06:56:52	ID requested
1	2023-04-18 18:22:32	announced
⏵ 2	2023-11-14 08:56:51	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: RNA processing, DIA, mitochondria, gene expression,Prostate cancer susceptibility

Aleksandra Filipovska
contact affiliation	Harry Perkins Institute of Medical Research and ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, Western Australia 6009, Australia
contact email	aleksandra.filipovska@uwa.edu.au
lab head
Timothy McCubbin
contact affiliation	University of Queensland
contact email	t.mccubbin@uq.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD033891
     1. Label: PRIDE project
     2. Name: Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer