A <i>HOTAIR</i> regulatory element modulates glioma cell sensitivity to temozolomide through long-range regulation of multiple target genes

Abstract

Temozolomide (TMZ) is a frequently used chemotherapy for glioma; however, chemoresistance is a major problem limiting its effectiveness. Thus, knowledge of mechanisms underlying this outcome could improve patient prognosis. Here, we report that deletion of a regulatory element in the <i>HOTAIR</i> locus increases glioma cell sensitivity to TMZ and alters transcription of multiple genes. Analysis of a combination of RNA-seq, Capture Hi-C, and patient survival data suggests that <i>CALCOCO1</i> and <i>ZC3H10</i> are target genes repressed by the <i>HOTAIR</i> regulatory element and that both function in regulating glioma cell sensitivity to TMZ. Rescue experiments and 3C data confirmed this hypothesis. We propose a new regulatory mechanism governing glioma cell TMZ sensitivity.