DGCR8 is essential for tumor progression following PTEN loss in the prostate. (23rd July 2015)

• Record Type: Journal Article
• Authors: Belair, Cassandra D; Paikari, Alireza; Moltzahn, Felix; Shenoy, Archana; Yau, Christina; Dall'Era, Marc; Simko, Jeff; Benz, Christopher; Blelloch, Robert
• Is Part Of: EMBO reports. Volume 16:Number 9(2015:Sep.)
• Page Start: 1219
• Page End: 1232
• Publication Date: 2015-07-23
• Subjects: Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201439925
• Languages: English
• ISSNs: 1469-221X

Abstract

<abstract abstract-type="main" id="embr201439925-abs-0001"> <title>Abstract</title> <p>In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the <italic>Dgcr8</italic> gene, a critical component of this complex, inhibits tumor progression in a <italic>Pten</italic>‐knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. <italic>Dgcr8</italic> loss blocked <italic>Pten</italic> null‐induced expansion of the basal‐like, but not luminal, cellular compartment. Furthermore, while late‐stage <italic>Pten</italic> knockout tumors exhibit decreased senescence‐associated beta‐galactosidase activity and increased proliferation, the simultaneous deletion of <italic>Dgcr8</italic> blocked these changes resulting in levels similar to wild type. Sequencing of small RNAs in isolated epithelial cells uncovered numerous miRNA changes associated with PTEN loss. Consistent with a <italic>Pten–Dgcr8</italic> association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for microRNAs in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following <italic>Pten</italic> loss.</p> </abstract>