A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell Carcinoma.

Abstract

Long noncoding RNAs (lncRNA) have been shown to play critical roles in many diseases, including esophageal squamous cell carcinoma (ESCC). Recent studies have reported that some lncRNA encode functional micropeptides. However, the association between ESCC and micropeptides encoded by lncRNA remains largely unknown. In this study, we characterized a Y-linked lncRNA, <i>LINC00278</i>, which was downregulated in male ESCC. <i>LINC00278</i> encoded a Yin Yang 1 (YY1)-binding micropeptide, designated YY1BM. YY1BM was involved in the ESCC progression and inhibited the interaction between YY1 and androgen receptor (AR), which in turn decreased expression of <i>eEF2K</i> through the AR signaling pathway. Downregulation of YY1BM significantly upregulated <i>eEF2K</i> expression and inhibited apoptosis, thus conferring ESCC cells more adaptive to nutrient deprivation. Cigarette smoking decreased m⁶A modification of <i>LINC00278</i> and YY1BM translation. In conclusion, these results provide a novel mechanistic link between cigarette smoking and AR signaling in male ESCC progression. SIGNIFICANCE: Posttranscriptional modification of a micropeptide-encoding lncRNA is negatively impacted by cigarette smoking, disrupting negative regulation of the AR signaling pathway in male ESCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2790/F1.large.jpg.<i>See related commentary by Banday et al., p. 2718</i>.