Targeting the mitochondrial RNA methyltransferase TRMT61B reveals new therapeutic opportunities in aneuploid cancer cells

Abstract

Chromosomal instability (CIN) is an important source of genetic and phenotypic variation that has been extensively reported as a critical cancer related property that improves tumor cell adaptation and survival. CIN and its immediate consequence, aneuploidy, provoke adverse effects on cellular homeostasis that need to be overcome by developing efficient anti-stress mechanisms. Perturbations in these safeguard responses might be detrimental for cancer cells and represent an important tumor specific Achilles heel since CIN and aneuploidy are very rare events in normal cells. On the other hand, epitranscriptomic marks catalyzed by different RNA modifying enzymes have been found to change under several stress insults. Although CIN and aneuploidy are important intracellular stressors, their biological connection with RNA modifications is pending to be determined. In an in silico search for new cancer biomarkers, we have identified TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. In the present work, we study the connection of this molecule with cancer and aneuploidy. First, we show increased protein amounts of TRMT61B in tumor cell lines with imbalanced karyotype as well as in different tumor types compared to unaffected control tissues. In addition, we demonstrate that depletion of TRMT61B in melanoma cells reduces cell proliferation either by fostering apoptosis and inhibiting autophagy in high-aneuploid (ANEhigh) cells or by inducing senescence in the case of low-aneuploid (ANElow) cell lines. Further, TRMT61B elimination compromises mitochondrial function and reduces the expression of several mitochondrial encoded proteins that are part of the electron transport chain. Finally, transwell and xenograft experiments revealed a reduced invasive and tumorigenic capacity upon TRMT61B depletion that strengthen the therapeutic value of this aneuploidy-associated biomarker. These results, which connect tumorigenesis, aneuploidy and mitochondrial RNA methylation, bring to the cancer field a new putative strategy to specifically target high aneuploid tumors.