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

Abstract

Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking. We used CRISPR‐Cas9 genome editing to introduce a missense variant identified in the ELAC2 gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouse Elac2 gene as well as to generate a prostate‐specific knockout of Elac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. 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. Multiomic profiling revealed defects in energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired noncoding RNA processing and reduced protein synthesis. Our physiologically relevant models show that the ELAC2 variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer.

Illuminating mitochondrial translation through mouse models

“…Interestingly, a common genetic variant in the MRPP3 gene [ 58 ], was functionally validated as a predisposing factor for high fat-diet induced insulin resistance, due to a moonlighting role of the RNase P complex with the LETM1 cation transporter [ 59 ]. Another common genetic variant identified in ELAC2 as the second most common susceptibility factor for prostate cancer [ 60 ] was introduced recently in mice [ 61 ]. The Ala541Thr variant led to reduced ELAC2 activity that resulted in impaired mitochondrial and nuclear tRNA processing and validated the role of ELAC2 [ 50 ], causing prostate hyperplasia and inflammation with age, but not prostate cancer [ 61 ].…”

“…Another common genetic variant identified in ELAC2 as the second most common susceptibility factor for prostate cancer [ 60 ] was introduced recently in mice [ 61 ]. The Ala541Thr variant led to reduced ELAC2 activity that resulted in impaired mitochondrial and nuclear tRNA processing and validated the role of ELAC2 [ 50 ], causing prostate hyperplasia and inflammation with age, but not prostate cancer [ 61 ]. Prostate-specific deletion of Elac2 resulted in similar defects and prostate inflammation.…”