Y Chromosome LncRNA Are Involved in Radiation Response of Male Non-Small Cell Lung Cancer Cells.

Abstract

Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome-expressed long noncoding RNA (lncRNA) that are involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of <i>linc-SPRY3-2/3/4</i> following irradiation, which was 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 <i>linc-SPRY3-2/3/4</i> transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for <i>linc-SPRY3-2/3/4</i> RNA. The presence of <i>linc-SPRY3-2/3/4</i> reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic <i>HMGA2</i> mRNA, as well as the oncogenic <i>c-MYC</i> mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of <i>linc-SPRY3-2/3/4</i> in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or <i>linc-SPRY3-2/3/4</i> and overall survival. Thus, <i>linc-SPRY3-2/3/4</i> expression and LOY could represent an important marker of radiotherapy in NSCLC. SIGNIFICANCE: This study describes previously unknown Y chromosome-expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4046/F1.large.jpg.