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 MYCoverexpressing 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.

Undermining ribosomal RNA transcription in both the nucleolus and mitochondrion : an offbeat approach to target MYC-driven cancer / S. Rossetti, A.J. Wierzbicki, N. Sacchi. - In: ONCOTARGET. - ISSN 1949-2553. - 9:4(2018), pp. 5016-5031. [10.18632/oncotarget.23579]

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

N. Sacchi
2018

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 MYCoverexpressing 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.
MYC-driven proliferation; Pol I and POLRMT inhibitors; Pol I-nucleolar rRNA transcription; POLRMT-mitochondrial rRNA transcription; Oncology
Settore BIO/11 - Biologia Molecolare
2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/623708
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