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, LINC00278, which was downregulated in male ESCC. LINC00278 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 eEF2K through the AR signaling pathway. Downregulation of YY1BM significantly upregulated eEF2K expression and inhibited apoptosis, thus conferring ESCC cells more adaptive to nutrient deprivation. Cigarette smoking decreased m6A modification of LINC00278 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.See related commentary by Banday et al., p. 2718.
Highlights
Esophageal squamous cell carcinoma (ESCC) is two to four times more common in men than in women worldwide [1]
We found 51 differentially expressed Long noncoding RNAs (lncRNA) were present in the male group, but not in the female group, and 3 of them were mapped to Y chromosome (Fig. 1B–D)
YY1-blocking micropeptide (YY1BM) blocked Yin Yang 1 (YY1) binding to androgen receptor (AR) to activate the expression of eEF2K, which is a key regulator for male ESCC progression
Summary
Esophageal squamous cell carcinoma (ESCC) is two to four times more common in men than in women worldwide [1]. Previous studies suggest that several male-specific factors contribute to such gender disparity, including cigarette smoking and sexual hormone. A survey in 2010 indicated that 52.9% of Chinese men while only 2.4% of Chinese women were current smokers [2, 3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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