Global transcriptional downregulation of TREX and nuclear trafficking machinery as pan-senescence phenomena: evidence from human cells and tissues

Abstract

Nucleocytoplasmic trafficking (NCT) of macromolecules is a fundamental process in eukaryotes that requires tight controls to maintain proper cell functions. Downregulation of the classical NCT pathway in senescent cells has been reported. However, whether this is a hallmark that exists across all types of cellular senescence remains unknown, and whether the mRNA export machinery is altered during senescence has not been demonstrated. Here, we show that the global transcriptomic downregulation of both the TREX (transcription-export) machinery and classical NLS-dependent protein transport machinery is a hallmark of varying types of senescence. A gene set-based approach using 25 different studies showed that the TREX-NCT gene set displays distinct common downregulated patterns in senescent cells versus its expression in their nonsenescent counterparts regardless of the senescence type, such as replicative senescence (RS), tumor cell senescence (TCS), oncogene-induced senescence (OIS), stem cell senescence (SCS), progeria and endothelial cell senescence (ECS). Similar patterns of TREX-NCT gene downregulation were also shown in two large human tissue genomic databases, the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. We also found that early-stage cancer tissues show consistent age-related patterns of TREX-NCT enrichment, suggesting the potential significance of TREX-NCT genes in determining cell fate in the early stage of tumorigenesis. Moreover, human cancer tissues exhibit an opposite TREX-NCT enrichment pattern with aging, indicating that deviation from age-related changes in TREX-NCT genes may provide a novel but critical clue for the age-dependent pathogenesis of cancer and increase in cancer incidence with aging.

Aging: Slowing down of nucleocytoplasmic trafficking

Proteins that move genetic information out of the nucleus and into the rest of the cell may be important in aging, and serve as markers of early-stage cancer. DNA is stored in the cell’s nucleus, and the messages which it encodes must be exported from the nucleus for gene expression. Aging is thought to be linked to a decrease in this export, but the exact mechanism remains unclear. Sung Young Kim, Konkuk University School of Medicine, Seoul, South Korea, and co-workers investigated key nuclear export proteins in healthy, cancerous, and aging cells. They found that nuclear export is strongly decreased in aging cells and shows distinctive patterns in very-early-stage cancer cells. These results shed further light on the cellular basis of aging, and may provide novel biomarkers for early cancer detection.