Exploring the Transcriptional Landscape of Epithelial Tumors in order to Decipher the Roleof Nonsense-mediated mRNA Decay in Cancer

Abstract

Nonsense-mediated mRNA decay (NMD) plays a crucial role in normal physiological processes by co-regulating the expression of a wide group of genes including cancer-related pathways. Although the role of NMD in cancer is integral, its exact contribution is often regarded as paradoxical with NMD playing both tumor-promoting and tumor-suppressing roles. The development of more effective cancer treatment strategies demands a better understanding of the impact of NMD in cancer. The current study explores the role of NMD in the context of cancer by analysing the functional outcomes of alternative splicing coupled NMD in 10 epithelial cancers. It makes use of isoform switching analysis and weighted gene co-expression network analysis to identify a set of pan-cancer-wide switching hub genes. The study reports 6 NMD-sensitive hub genes across multiple carcinomas, with 4 genes being directly or indirectly involved in tumorigenesis. Notably, the findings support an anti-tumorigenic role of NMD as evidenced by the downregulation of potentially oncogenic isoforms of TIMM17B and FAM136A genes as well as increased isoform usage of potentially tumor-suppressing ZNRD1 gene. However, the results also report the upregulation in the isoform usage of proteincoding isoforms of CDK20, a potentially oncogenic gene. It can be concluded that cancer genes possess the capacity to manipulate NMD processes, thereby contributing to tumor progression. Consistent with the prevailing view, this research substantiates both pro- and anti-tumorigenic functions of NMD in cancer. Nevertheless, it broadens our understanding of the nuanced interplay between NMD and cancer genes.