At the Japanese Foundation for Cancer Research (JFCR), scientists have discovered that noncoding RNA (ncRNA) derived from pericentromeric repetitive elements can provoke inflammatory gene expression during senescence and cancer. Ordinarily, in young cells, these elements are silenced by the CCCTC-binding factor (CTCF). However, in senescent cells, ncRNA derived from these elements directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of inflammatory genes, promoting the senescence-associated secretory phenotype (SASP).
Senescence is a state of essentially irreversible cell cycle arrest induced by several stressors, that is, aging, obesity, radiation, and chemotherapy. Senescent cells that accumulate in vivo during aging communicate with surrounding tissues through the production of proinflammatory proteins, giving rise to SASP, which plays multiple physiological and pathological roles. In aged individuals, inflammatory SASP factors promote numerous age-related diseases, including cancer. Therefore, elucidating the regulatory mechanism of the SASP is essential for developing new preventive and therapeutic strategies against age-related cancer.
Regulatory mechanisms uncovered by the JFCR researchers were detailed in an article (“Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer”) that appeared this week in the Proceedings of the National Academy of Sciences USA. This article reported that in cellular senescence, pericentromeric ncRNA is transferred into surrounding cells via small extracellular vesicles (EVs) and functions as a tumorigenic SASP factor.
“Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the downregulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression,” the article’s authors wrote. “In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non–cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.”
To generate these findings, the JFCR researchers used next-generation sequencing to analyze genome-wide chromatin interaction and gene expression. The researchers focused on a genomic region called human satellite II (hSATII), which contains pericentromeric repetitive sequences. These regions, which are epigenetically silenced in normal cells, showed a notably open state in senescent cells.
In addition, the JFCR researchers observed that the expression of noncoding RNA (hSATII RNA) was markedly upregulated during cellular senescence. Further analysis revealed that hSATII RNA upregulated SASP-like inflammatory gene expression by disturbing chromatin interactions in some SASP gene regions through the functional impairment of CTCF, which is important for the maintenance of genomic integrity.
“Intriguingly, the amounts of hSATII RNA were higher in small EVs derived from senescent cells than in those derived from proliferating cells,” the article’s authors noted. “Thus, our data suggest that hSATII RNA derived from senescent stromal cells are transferred into surrounding cells through small EVs and function as a SASP-like inflammatory factor in the tumor microenvironment.”
Further, the researchers found that hSATII RNA was highly detectable in cancer cells in surgical specimens from patients with primary colon carcinoma. Strikingly, the population of hSATII RNA-positive cells was significantly higher among cancer-associated fibroblasts than fibroblasts in normal stromal tissues.
“These findings highlight the new role of the hSATII RNA, which supports tumor development in a non–cell-autonomous manner via the secretion of SASP-like inflammatory factors and small EVs,” the JFCR scientists concluded. “Understanding this molecular mechanism can facilitate the development of novel preventive and therapeutic strategies against age-related pathologies in the future.”