DGCR8 is essential for tumor progression following PTEN loss in the prostate

Cassandra D. Belair, Alireza Paikari, Felix Moltzahn, Archana Shenoy, Christina Yau, Marc Dall'Era, Jeff Simko, Christopher Benz, Robert Blelloch

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten-knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null-induced expansion of the basal-like, but not luminal, cellular compartment. Furthermore, while late-stage Pten knockout tumors exhibit decreased senescence-associated beta-galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 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 Pten-Dgcr8 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 Pten loss. Synopsis This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia. DGCR8 loss prevents growth and progression of Pten null prostate tumors. DGCR8 loss mainly inhibits expansion of the basal cell compartment of the Pten null epithelium. Small RNA sequencing reveals numerous microRNA level changes associated with PTEN loss. Increases in DGCR8 are associated with AKT activation in a large cohort of human patient samples. This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia.

Original languageEnglish (US)
Pages (from-to)1219-1232
Number of pages14
JournalEMBO Reports
Volume16
Issue number9
DOIs
StatePublished - Sep 1 2015

Keywords

  • DGCR8
  • microRNA
  • microRNA biogenesis
  • prostate cancer
  • PTEN

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry

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  • Cite this

    Belair, C. D., Paikari, A., Moltzahn, F., Shenoy, A., Yau, C., Dall'Era, M., Simko, J., Benz, C., & Blelloch, R. (2015). DGCR8 is essential for tumor progression following PTEN loss in the prostate. EMBO Reports, 16(9), 1219-1232. https://doi.org/10.15252/embr.201439925