Multi-omic profiling reveals an RNA processing rheostat that predisposes to prostate cancer

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Timothy McCubbin  

LAB HEAD: Aleksandra Filipovska

PROVIDER: PXD033891 | Pride | 2023-04-19

REPOSITORIES: Pride