N6-methyladenosine upregulates ribosome biogenesis in environmental carcinogenesis

Abstract

Many trace metal pollutants in surface water, the atmosphere, and soil are carcinogenic, and ribosome biogenesis plays an important role in the carcinogenicity of heavy metals. However, the contradiction between upregulated ribosome biogenesis and decreased ribosomal DNA copy number in environmental carcinogenesis is not fully understood. Here, from a perspective of the most predominant and abundant RNA epigenetic modification, N⁶-methyladenosine (m⁶A), we explored the reason behind this contradiction at the post-transcriptional level using arsenite-induced skin carcinogenesis models both in vitro and in vivo. Based on the m⁶A microarray assay and a series of experiments, we found for the first time that the elevated m⁶A in arsenite-induced transformation is mainly enriched in the genes regulating ribosome biogenesis. m⁶A upregulates ribosome biogenesis post-transcriptionally by stabilizing ribosomal proteins and modulating non-coding RNAs targeting ribosomal RNAs and proteins, leading to arsenite-induced skin carcinogenesis. Using multi-omics analysis of human subjects and experimental validation, we identified an unconventional role of a well-known key proliferative signaling node AKT1 as a vital mediator between m⁶A and ribosome biogenesis in arsenic carcinogenesis. m⁶A activates AKT1 and transmits proliferative signals to ribosome biogenesis, exacerbating the upregulation of ribosome biogenesis in arsenite-transformed keratinocytes. Similarly, m⁶A promotes cell proliferation by upregulating ribosome biogenesis in cell transformation induced by carcinogenic heavy metals (chromium and nickel). Importantly, inhibiting m⁶A reduces ribosome biogenesis. Targeted inhibition of m⁶A-upregulated ribosome biogenesis effectively prevents cell transformation induced by trace metals (arsenic, chromium, and nickel). Our results reveal the mechanism of ribosome biogenesis upregulated by m⁶A in the carcinogenesis of trace metal pollutants. From the perspective of RNA epigenetics, our study improves our understanding of the contradiction between upregulated ribosome biogenesis and decreased ribosomal DNA copy number in the carcinogenesis of environmental carcinogens.

Keywords: AKT1; Arsenic; Carcinogenicity; Heavy metal contaminants; Ribosomal proteins; m(6)A.