Epigenetic Effects of Ionizing Radiation

Abstract

Pancreatic cancer is associated with a high mortality rate, owing to de novo and acquired drug resistance, thereby leading to highly invasive and metastatic pancreatic cancer cells. Therefore, targeting pancreatic cancer stem cells (CSCs) may be a novel therapeutic strategy for the treatment of pancreatic cancer. Here, we combined a DNA methylation inhibitor (5-aza-2'-deoxycytidine; 5-aza-dC) and ionizing radiation (IR) to improve anti-cancer effects by inhibiting growth and proliferation and promoting apoptosis of pancreatic cancer cells in vitro and in vivo. Importantly, the combinatorial effect of 5-aza-dC with IR on sphere-forming pancreatic cancer cells was preferentially targeted toward CSCs through the downregulation of regulatory factors of self-renewal and CSC surface markers. We next performed the RNA sequencing to understand the underlying cellular mechanisms of the combined treatment with IR and 5-aza-dC in pancreatic cancer cells. Global transcriptome profiling indicated that the expression of the Oct4-centered transcriptional network of genes was significantly downregulated in cells with combination treatment. Our data suggested that combination treatment with DNA methylation inhibitor and IR may be a novel therapeutic strategy for pancreatic cancer. Overall, these findings support the use of epigenetic therapy in combination with radiotherapy to improve therapeutic efficacy by targeting and eradicating pancreatic CSCs.

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

“…As explained in the text, the sex-specific bystander effect that was reported by Koturbash et al [39,143] was observed together with DNA methylation changes. Studies have also shown that epigenetic changes were involved in both direct and indirect radiation effects [151]. Ilnytskyy and Kovalchuk [228] recently reviewed the role of DNA methylation and small RNAs in directly irradiated and bystander tissues and in radiation-induced transgenerational effects.…”

“…In contrast, the sex-specific bystander effect that was reported by Koturbash et al [39,143] was observed together with DNA methylation changes, which is an important epigenetic phenomenon that is involved in the regulation of gene expression and genome stability. In fact, evidence indicated that epigenetic changes were involved in both direct and indirect radiation effects [151]. Until now, few studies on epigenetic changes that were involved in the in vivo bystander effect have been performed.…”

A Perspective on Prevention of Wars and Pandemics with Lessons from the Case of Pellagra

“…Extraordinary differences on longevity and reaching retirement on good health occur even in rich countries (70% chance in affluent areas but half that at the opposite end of the wealth spectrum and not due to poor adult habits as the death rate at aged 8 is 10fold higher for the poor. These can be compared to 18th C statistics on elite enslaved workers with life expectancies of 60 years working domestically (and having access to leftovers) often lighter skimmed and field workers of 40 years; disadvantages that get passed down generations [48] Nicotinamide and methylation pathways are important epigenetic pathways and pellagra often appeared to be familial and transgenerational as well as linked to infection and relative energy [114][115][116][117]. This switch from infection to allergy and auto-immune disease was first seen in rich white well-fed communities.…”

Zebrafish as an In Vivo Model to Assess Epigenetic Effects of Ionizing Radiation

“…The relationship between epigenetics and IR was comprehensively reviewed [79,80,81]. Accumulating evidence has demonstrated that IR exposures can lead to epigenetic alterations, which play an important role in genomic instability that can affect the next generations [82,83,84].…”