Virginie MARCEL-TERRIER, Cancer Research Center of Lyon

Virginie MARCEL-TERRIER, invited by Guillaume LAMIRAULT (Eq IIa)
Nuclear domains and Pathologies team, Department of Cancer Cell Plasticity, Cancer Research Center of Lyon, UMR INSERM U1052 CNRS 5286, Université Lyon 1, Centre Léon Bérard, Lyon, France
Virginie.marcel@lyon.unicancer.fr

Abstract

Unexpected characteristics of the ribosome, the machinery that translates mRNAs into proteins, have been recently revealed that open up novel perspectives in the understanding of its biological function. First, it appears that translation reprogramming as a key role in cancer. Second, it emerges that ribosome plays key role in tumorigenesis since specific inhibition of ribosome biogenesis using anti-RNA polymerase I inhibitor targets cancer cells without affecting healthy cells. Finally, it emerges that ribosome is present as different variants, which displays distinct translational activity. The major source of ribosome heterogeneity comes from the ribosomal RNA (rRNA). Like proteins, rRNA exhibits chemical modifications, including 2’-O-ribose methylation (or methylation). These modifications have a key role in maintaining ribosome structure and thus affect its translational activity (Lo Monaco et al, Biomolecules 2018).  

We demonstrated for the first time that alteration of rRNA methylation occurs during tumor initiation and progression. In p53 inactivated mammary cells, modification of rRNA methylation is associated with change in translational control of a subset of mRNAs encoding oncogenic proteins that promote tumorigenesis (Marcel et al, Cancer Cell 2013). Recently, we firmly demonstrate that alteration of the rRNA methylation pattern induced by alteration of expression of fibrillarin (FBL), the unique rRNA methyl-transferase, directly affects translational control is (Erales et al, PNAS 2017). In parallel, development of RiboMeth-Seq, a genome-wide approach to study rRNA methylation, allowed us to determine that change in rRNA methylation occurs only at some given sites. In addition, RiboMeth-Seq technology allowed us to identify specific alterations occurring in the rRNA methylation pattern during particular biological processes involved in tumorigenesis and cancer development but also in human tumours.

We accumulated several evidences demonstrating for the first time that rRNA methylation pattern is affected in different tumoral models. Our data support the emerging notion of rRNA epigenetics claiming that chemical modifications of rRNA participate in gene-specific expression by modulating translation. They also support the major role of ribosome in tumorigenesis. Finally, it appears that the ribosome can be used as a clinical marker and that ribosome heterogeneity could provide novel and original anti-cancer therapeutic opportunities. 

Selected references

• Nguyen Van Long F, Lardy-Cleaud A, Bray S, Chabaud S, Dubois T, Diot A, Thompson AM, Bourdon JC, Perol D, Bouvet P, Diaz JJ and Marcel V. The druggable nucleolin identifies breast tumours associated with poor prognosis that exhibit different biological processes. Cancers (2018) 10, 390.
• Lo Monaco P, Marcel V, Diaz JJ and Catez F. 2’-O-Methylation of ribosomal RNA: Towards an epitranscriptomic control of translation ? Biomolecules (2018) (in press)
• Erales J, Marchand V, Panthu B, Gillot S, Belin S, Ghayad SE, Garcia M, Laforêts F, Marcel V, Baudin-Baillieu A, Bertin P, Coute Y, Adrait A, Meyer M, Therizols G, Yusupov M, Namy O, Ohlmann T, Motorin I, Catez F and Diaz JJ. Evidence for rRNA 2'-O-methylation plasticity: control of intrinsic translational capabilities of human ribosomes. PNAS (2017) vol 114(49):12934-12939.
• Bash-Imam Z*, Therizols G*, Vincent A, Lafôrets F, Polay Espinoza M, Pion N, Macari F, Pannequin J, David A, Saurin JC, Mertani HC, Textoris J, Auboeuf D, Catez F, Dalla Venezia N, Dutertre M*, Marcel V* and Diaz JJ*. Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism. Oncotarget (2017) vol 8(28), 46219-46233.
• Marcel V, Catez F, Berger CM, Perrial E, Plesa A, Thomas X, Mattei E, Hayette S, Saintigny P, Bouvet P, Diaz JJ* and Dumontet C*. Expression profiling of ribosome biogenesis factors reveals Nucleolin as a novel potential marker to predict outcome in AML patients. PLoS One (2017) vol 12(1), e0170160.
• Marcel V, Catez F and Diaz JJ. Ribosome heterogeneity in tumorigenesis: the rRNA point of view. Mol Cell Oncol (2015) vol 2(3), e983755.
• Marcel V, Ghayad SE, Belin S, Therizols G, Morel AP, Solano-Gonzàlez E, Vendrell JA, Hacot S, Mertani HC, Albaret MA, Bourdon JC, Jordan L, Thompson A, Tafer Y, Cong R, Bouvet P, Saurin JC, Catez F, Prats AC, Puisieux A and Diaz JJ. p53 acts as a safeguard of translational control by regulating Fibrillarin and rRNA methylation in cancer. Cancer Cell (2013) vol 24(3), 318–330.
• Marcel V, Catez F and Diaz JJ. Ribosomes: the future of targeted therapies? Oncotarget (2013) vol 4(10), 1554–1555.