LY6K promotes glioblastoma tumorigenicity via CAV-1–mediated ERK1/2 signaling enhancement. Issue 9 (14th February 2020)

• Record Type: Journal Article
• Authors: Sastry, Namratha G; Wan, Xuechao; Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P; Song, Xiao; James, Charles David; Horbinski, Craig M; Brennan, Cameron W; Nakano, Ichiro; Hu, Bo; Cheng, Shi-Yuan
• Is Part Of: Neuro-oncology. Volume 22:Issue 9(2020)
• Page Start: 1315
• Page End: 1326
• Publication Date: 2020-02-14
• Subjects: LY6K -- glioblastoma -- ERK1/2 -- CAV-1 -- methylation; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa032
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Lymphocyte antigen 6 complex, locus K ( LY6K ) is a putative oncogene in various cancers. Elevated expression of LY6K is correlated with poor patient prognosis in glioblastoma (GBM). The aim of this study is to advance our understanding of the mechanism by which LY6K contributes to GBM tumor biology. Methods: Bioinformatic data mining was used to investigate LY6K expression in relation to GBM clinical outcome. To understand the role of LY6K in GBM, we utilized patient-derived glioma stemlike cells (GSCs) and U87 cells and employed immunoblotting, immunofluorescent staining, radiation treatment, and orthotopic GBM xenograft models. Results: Our results show that increased expression of LY6K inversely correlates with GBM patient survival. LY6K promotes tumorigenicity in GBM cells both in vitro and in vivo. The mechanism underlying this tumorigenic behavior is enhancement of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Interestingly, we observed that tumor-promoting LY6K-ERK1/2 signaling is mediated by the interaction of LY6K with caveolin-1, rather than through oncogenic receptor tyrosine kinase–mediated signaling. Moreover, association of LY6K with the cell membrane is crucial for its tumorigenic functions. Finally, DNA methylation maintains LY6K silencing, and hypomethylation of the LY6K promoter increases its expression. In GSCs, ionizing radiation leads to demethylation of the LY6K promoter, thereby increasing LY6K expression and GSC resistance to radiation. Conclusions: Our study highlights the importance of the contribution of LY6K to GBM tumor biology and suggests LY6K as a potential membrane target for treating GBM.