Yinghui Li¹, Zhen Wang¹, Hui Shi¹, Hang Li¹, Leilei Li¹, Runping Fang¹,Xiaoli Cai¹, Bowen Liu¹, Xiaodong Zhang^2,*, and Lihong Ye^1,*

Author Affiliations

*Corresponding Authors:
Lihong Ye, Nankai University, 94 Weijin Road, Tianjin 300071, China. Phone: 86-22-23501385; Fax: 86-22-23501385; E-mail: yelihong@nankai.edu.cn; and Xiaodong Zhang,zhangxd@nankai.edu.cn

Abstract

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 Res; 76(2); 293–304. ©2015 AACR.

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