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.

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Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be elucidated. Among them is the transcription factor NF-κB, which is known to play critical roles in cell survival, inflammation and immunity. Recent studies indicate that mammary epithelial NF-κB regulates the self-renewal of breast cancer stem cells in a model of Her2-dependent tumourigenesis. We will describe here the NF-κB-activating pathways that are involved in this process and in which progenitor cells this transcription factor is actually activated.

Constitutive activation of EGFR- and NF-κB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial–mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-κB activity that transmits pro-survival and invasive signals through EGFR signalling.

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

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9);

The nuclear and oncogenic BCL-3 protein activates or represses gene transcription when bound to NF-B proteins p50 and p52, yet the molecules that specifically interact with BCL-3 and drive BCL-3-mediated effects on gene expression remain largely uncharacterized. Moreover, GSK3-mediated phosphorylation of BCL-3 triggers its degradation through the proteasome, but the proteins involved in this degradative pathway are poorly characterized. Biochemical purification of interacting partners of BCL-3 led to the identification of CtBP as a molecule required for the ability of BCL-3 to repress gene transcription. CtBP is also required for the oncogenic potential of BCL-3 and for its ability to inhibit UV-mediated cell apoptosis in keratinocytes. We also defined the E3 ligase TBLR1 as a protein involved in BCL-3 degradation through a GSK3-independent pathway. Thus, our data demonstrate that the LSD1/CtBP complex is required for the repressing abilities of an oncogenic IB protein, and they establish a functional link between the E3 ligase TBLR1 and NF-B.