Effects on prostate cancer cells of targeting RNA polymerase III

Nucleic Acids Res. 2019 May 7;47(8):3937-3956. doi: 10.1093/nar/gkz128.

Abstract

RNA polymerase (pol) III occurs in two forms, containing either the POLR3G subunit or the related paralogue POLR3GL. Whereas POLR3GL is ubiquitous, POLR3G is enriched in undifferentiated cells. Depletion of POLR3G selectively triggers proliferative arrest and differentiation of prostate cancer cells, responses not elicited when POLR3GL is depleted. A small molecule pol III inhibitor can cause POLR3G depletion, induce similar differentiation and suppress proliferation and viability of cancer cells. This response involves control of the fate-determining factor NANOG by small RNAs derived from Alu short interspersed nuclear elements. Tumour initiating activity in vivo can be reduced by transient exposure to the pol III inhibitor. Untransformed prostate cells appear less sensitive than cancer cells to pol III depletion or inhibition, raising the possibility of a therapeutic window.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alu Elements / drug effects
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Prostatectomy
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / surgery
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Polymerase III / antagonists & inhibitors
  • RNA Polymerase III / genetics*
  • RNA Polymerase III / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Small Molecule Libraries / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Heat-Shock Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Protein Isoforms
  • RNA, Small Interfering
  • Small Molecule Libraries
  • POLR3G protein, human
  • RNA Polymerase III
  • molecular chaperone GRP78