Cancer Cell 25, 77–90 (2014)

Credit: ELSEVIER

In cancer cells, nucleolar activity and ribosomal RNA (rRNA) synthesis by RNA polymerase I (Pol I) are increased. Therefore, compounds that can reduce rRNA synthesis could be considered for therapeutics. The small molecule BMH-21 reduces viability in a wide variety of cancer cell lines and blocks in vivo tumor growth in a p53-independent manner, but the mechanism of action has remained unclear. Peltonen et al. observed that BMH-21 is a DNA-intercalating agent that binds to GC-rich regions of DNA. In particular, BMH-21 exhibited specific binding to rDNA, resulting in the rapid inhibition of Pol I transcriptional activity. This loss of transcription was associated with increased detection of nucleolar stress in cells characterized by structural changes in the nucleolus and mislocalization of nucleolar proteins such as nucleolin and nucleophosmin. In addition, BMH-21 treatment resulted in the polyubiquitination and proteasomal degradation of RPA194, the largest catalytic subunit of Pol I. The loss of RPA194 expression prevented the Pol I complex from binding to rDNA and correlated well with decreased cancer cell survival. Taken together, this work suggests that inhibiting components of the ribosomal RNA synthesis machinery may be an effective strategy for future cancer therapeutics.