Gene Therapy Unit, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
Cell Death Differ. 2023 Jan;30(1):37-53. doi: 10.1038/s41418-022-01044-6. Epub 2022 Jul 22.
Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.
尽管染色体不稳定（CIN）及其直接后果——非整倍体经常在癌细胞中观察到，但它们会引发对细胞稳态的不利影响，需要通过抗应激机制来克服。因此，这些保护反应代表了肿瘤特有的阿喀琉斯之踵，因为在正常细胞中很少观察到 CIN 和非整倍体。最近的数据表明，RNA 修饰酶催化的转录后修饰标记在各种应激损伤下发生变化。然而，非整倍体是否与这些 RNA 修饰途径有关仍有待确定。通过在癌细胞中寻找非整倍体生物标志物的计算搜索，我们发现 TRMT61B，一种线粒体 RNA 甲基转移酶酶，与高水平的非整倍体有关。因此，TRMT61B 蛋白水平在具有不平衡染色体组型的肿瘤细胞系以及与对照组织相比的不同肿瘤类型中增加。有趣的是，虽然 TRMT61B 耗竭在非整倍体水平低的黑色素瘤细胞系中诱导衰老，但在高水平的细胞中导致细胞凋亡。通过在 transwell 和异种移植测定中靶向 TRMT61B 进一步验证了这些结果的治疗潜力。我们表明，TRM61B 耗竭降低了几种线粒体编码蛋白的表达并限制了线粒体功能。总之，这些结果确定了癌细胞中非整倍体的新生物标志物，它可能被用于有针对性地靶向高度非整倍体肿瘤。
