Oncotarget

Research Papers:

Undermining ribosomal RNA transcription in both the nucleolus and mitochondrion: an offbeat approach to target MYC-driven cancer

Stefano Rossetti, Andrzej J. Wierzbicki and Nicoletta Sacchi _

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Oncotarget. 2018; 9:5016-5031. https://doi.org/10.18632/oncotarget.23579

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Abstract

Stefano Rossetti1, Andrzej J. Wierzbicki1 and Nicoletta Sacchi1

1Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

Correspondence to:

Nicoletta Sacchi, email: nicoletta.sacchi@roswellpark.org

Keywords: Pol I-nucleolar rRNA transcription; POLRMT-mitochondrial rRNA transcription; MYC-driven proliferation; Pol I and POLRMT inhibitors

Received: September 18, 2017     Accepted: December 09, 2017     Published: December 22, 2017

ABSTRACT

The MYC transcription factor coordinates, via different RNA polymerases, the transcription of both ribosomal RNA (rRNA) and protein genes necessary for nucleolar as well as mitochondrial ribogenesis. In this study we tested if MYC-coordination of rRNA transcription in the nucleolus and in the mitochondrion drives (cancer) cell proliferation. Here we show that the anti-proliferative effect of CX-5461, a Pol I inhibitor of rRNA transcription, in ovarian (cancer) cell contexts characterized by MYC overexpression is enhanced either by 2’-C-Methyl Adenosine (2’-C-MeA), a ribonucleoside that inhibits POLRMT mitochondrial rRNA (mt-rRNA) transcription and doxycycline, a tetracycline known to affect mitochondrial translation. Thus, hindering not only mt-rRNA transcription, but also mitoribosome function in MYC-overexpressing ovarian (cancer) cells, potentiates the antiproliferative effect of CX-5461. Targeting MYC-regulated rRNA transcription and ribogenesis in both the nucleolus and mitochondrion seems to be a novel approach worth of consideration for treating MYC-driven cancer.


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