14The deposition of chemical modifications into RNA is a crucial regulator of temporal and 15 spatial accurate gene expression programs during development. Accordingly, altered RNA 16 modification patterns are widely linked to developmental diseases. Recently, the 17 dysregulation of RNA modification pathways also emerged as a contributor to cancer. By 18 modulating cell survival, differentiation, migration, and resistance, RNA modifications add a 19 novel regulatory layer of complexity to most aspects of tumourigenesis. 20 21 deposition of the modifications (Figure 1a). The modifications range from simple 47 methylation or isomerization events, such as m 5 C, m 1 A, Ψ, 5-methyluridine (m 5 U), 1-and 48 1/7-methylguanosine (m 1 G, m 7 G), and inosine, to complex multistep chemical modifications, 49 such as N6-threonylcarbamoyladenosine (t 6 A) and 5-methoxycarbonylmethyl-2-thiouridine 50 (mcm 5 s 2 U) 5 . 51 52The most abundant internal modification in mRNA (and also long non-coding RNA) is N6-53 methyladenosine (m 6 A) 8-11 . Around 0.1 to 0.4% of all mRNA adenines are methylated, 54 representing approximately 3-5 modifications per mRNA [11][12][13] . Other rarer modifications 55 within eukaryotic mRNA include N1-methyladenosine (m 1 A), N6-2'O-dimethyladenosine 56 (m 6 A m ), 5-methycytosine (m 5 C), 5-hydroxymethylcytosine (hm 5 C), and pseudouridine (Ψ) 57 (Figure 1b) [14][15][16][17][18][19][20][21] . Some of these modifications are generated by stand-alone enzymes 22 , 58 others are installed by multi-protein writer complexes and accessory subunits (Figure 1b) 23 . 59 60 RNA modifications modulate gene expression programs 61The first step of gene expression is the transcription of DNA molecules into mRNA. The 62 deposition of m 6 A into nascent pre-mRNA is carried out in the nucleus by a multicomponent 63 methyltransferase complex 24,25 . The multi-protein writer complex installing m 6 A consists of 64 the Methyltransferase Like catalytic subunits (METTL3, METTL14), and many other 65 accessory subunits 23 . Gene-specific transcription factors and chromatin modifying enzymes 66 can further modulate the deposition of m 6 A into nascent RNA by repelling or recruiting the 67 m 6 A writer complex [26][27][28] . 68 69 Two demethylases, Fat Mass and Obesity-associated protein (FTO) and AlkB Homolog 5 70 (ALKBH5) act as erasers of the m 6 A modification (Figure 2a) 29,30 . Several reader proteins 71

Reprogramming of mRNA translation has a key role in cancer development and drug resistance . However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U) tRNA (U enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF oncogene and by resistance to targeted therapy in melanoma. We show that BRAF -expressing melanoma cells are dependent on U enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U enzymes. Mechanistically, U enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U enzymes and HIF1α. Together, these results demonstrate that U enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.

Delaunay et al. reveal the role of U34 tRNA-modifying enzymes in the regulation of specific mRNA translation to support cell invasion and metastasis.

Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications—5-methylcytosine (m5C) and its derivative 5-formylcytosine (f5C) (refs.2–4)—drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m5C at position 34 in mitochondrial tRNAMet. m5C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m5C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m5C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.

Ladang et al. report that Elp3, a subunit of the Elongator complex, is induced by Wnt signaling and is required to initiate colon cancer development through the regulation of Sox9 translation. They also show that this mechanism is relevant in radiation-induced intestinal regeneration.

No abstract

MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here, we demonstrate that -mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a β-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAF-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis. CEMIP silencing circumvented resistance to MEK1 inhibition, partly, through a decrease of both ERK1/2 signaling and c-Myc. Together, our data identify a cross-talk between Wnt and MAPK signaling cascades, which involves CEMIP. Activation of this pathway promotes survival by potentially regulating levels of specific amino acids via a Myc-associated cascade. Targeting this node may provide a promising avenue for treatment of colon cancers that have acquired resistance to targeted therapies. MEK1 inhibitor-resistant colorectal cancer relies on the scaffold and endosomal protein CEMIP to maintain ERK1/2 signaling and Myc-driven transcription. .

No abstract