TRM6/61 connects PKC alpha with translational control through tRNA sub(i) super(Met) stabilization: impact on tumorigenesis

• Published in: Oncogene Vol. 35; no. 14; pp. 1785 - 1796
• Main Authors: Macari, F, El-houfi, Y, Boldina, G, Xu, H, Khoury-Hanna, S, Ollier, J, Yazdani, L, Zheng, G, Bieche, I, Legrand, N, Paulet, D, Durrieu, S, Bystrom, A, Delbecq, S, Lapeyre, B, Bauchet, L, Pannequin, J, Hollande, F, Pan, T, Teichmann, M, Vagner, S, David, A, Choquet, A, Joubert, D
• Format: Journal Article
• Language: English
• Published: 07.04.2016
• ISSN: 0950-9232
• DOI: 10.1038/onc.2015.244

Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C alpha (PKC alpha ) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNA sub(i) super(Met)), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNA sub(i) super(Met). In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNA sub(i) super(Met)- overexpressing cells, PKC alpha overexpression decreased tRNA sub(i) super(Met) expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNA sub(i) super(Met) expression with decreased expression of PKC alpha mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKC alpha tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.