Abstract
Approximately 50% of melanoma patients carry a mutation in the BRAF gene, and over 90% of these mutations lead to the substitution of valine 600 with glutamic acid (V600E). Vemurafenib is an FDA-approved kinase inhibitor for BRAF(V600E); while the drug elicits effective remission of metastatic melanoma, relapse typically occurs within several months after therapy. Recent studies documented critical roles of reversible modifications in RNA in modulating resistance to cancer therapy. Herein we explored the contributions of epitranscriptomic alterations to vemurafenib resistance by assessing the differential expression of epitranscriptomic reader, writer and eraser (RWE) proteins in IGR37 metastatic melanoma cells and the isogenic vemurafenib-resistant cells (IGR37xp). Our results revealed altered expressions of multiple epitranscriptomic RWE proteins, including markedly elevated expressions of MTO1 and TRMU─which act sequentially to produce 5-taurinomethyl-2-thiouridine (τm(5)s(2)U) at the 34th position of human mitochondrial (mt) tRNA(Glu), tRNA(Gln) and tRNA(Lys)─in the resistant line. We also observed elevated oxidative phosphorylation in IGR37xp relative to IGR37 cells. Moreover, we found that genetic depletion of TRMU in IGR37xp cells results in diminished oxidative phosphorylation and resensitizes IGR37xp cells to vemurafenib. Together, we uncovered a role of TRMU in conferring vemurafenib resistance in melanoma through modulating oxidative phosphorylation.