HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c Myc.
c Myc is regarded as a transcription factor, but the basis for its function remains unclear. Here, we define a long noncoding RNA (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. We 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 upregulation of these target genes. Mechanistically, HBXIP interacted directly with c Myc through the leucine zippers and recruited the lncRNA 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.
Cancer research