Evidence of Y Chromosome LncRNAs involved in Radiation Response of Male Non-Small Cell Lung Cancer Cells

Numerous studies have implicated changes in the Y chromosome in male cancers, however few have investigated the biological importance of Y chromosome non-coding RNAs. Here, we demonstrate a group of Y chromosome-expressed long non-coding RNAs (lncRNAs) involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. UV Cross-linking and Immunoprecipitation (CLIP) and RNA stability assays identify IGF2BP3 as a binding partner for the linc-SPRY3-2/3/4 RNAs which alters the half-life of the anti-apoptotic HMGA2 mRNA as well as the oncogenic c-MYC mRNA. To assess the clinical relevance of these findings, we examined the presence of the Y chromosome in NSCLC tissue microarrays and the expression of linc-SPRY3-2/3/4 in NSCLC RNAseq and microarray data. We observed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiation therapy in NSCLC.

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Brownmiller T, Juric JA, Ivey AD, Harvey BM, Westemeier ES, Winters MT, Stevens AM, Stanley AN, Hayes KE, Sprowls SA, Ammer ASG, Walker M, Bey EA, Wu X, Lim ZF, Zhu L, Wen S, Hu G, Ma PC, Martinez I