HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc

C-Myc is regarded a transcription factor but the basis for its function remains unclear. Here we define a lncRNA/protein complex that mediates the transcriptional activation by c-Myc in breast cancer cells. Among 388 c-Myc target genes in human MCF-7 breast cancer cells, we found that their promoters could be occupied by the oncoprotein HBXIP. In clinical breast tumor specimens, confirmed that the HBXIP expression correlated with expression of the c-Myc target genes Cyclin A, eIF4E and LDHA. RNAi-mediated silencing of HBXIP abolished c-Myc-mediated up-regulation of these target genes. Mechanistically, HBXIP interacted directly with c-Myc through the leucine zippers and recruited the long noncoding RNA Hotair along with the histone demethylase LSD1, for which Hotair serves as a scaffold. Silencing of HBXIP, Hotair or LSD1 was sufficient to block c-Myc-enhanced cancer cell growth in vitro and in vivo. Taken together, our results support a model in which the HBXIP/Hotair/LSD1 complex serves as a critical effector of c-Myc in activating transcription of its target genes, illuminating long-standing questions on how c-Myc drives carcinogenesis.