G-quadruplex is critical to epigenetic activation of the lncRNA HOTAIR in cancer cells
Xiaohan Qu,
Zhen Lin,
Janarthanan Jayawickramarajah,
John S. Alsager,
Emily Schmidt,
Kenneth P. Nephew,
Fang Fang,
Shankar Balasubramanian,
Bin Shan
Affiliations
Xiaohan Qu
Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Corresponding author
Zhen Lin
Deparmtent of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Janarthanan Jayawickramarajah
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
John S. Alsager
Department of Biomedical Sciences, Elson S Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
Emily Schmidt
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
Kenneth P. Nephew
Medical Sciences, Cell and Molecular Cancer Biology Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
Fang Fang
Medical Sciences, Cell and Molecular Cancer Biology Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
Shankar Balasubramanian
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK; Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Bin Shan
Department of Biomedical Sciences, Elson S Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
Summary: The cancer-promoting lncRNA HOTAIR has multiple isoforms. Which isoform of HOTAIR accounts for its expression and functions in cancer is unknown. Unlike HOTAIR’s canonical intergenic isoform NR_003716 (HOTAIR-C), the novel isoform NR_047517 (HOTAIR-N) forms an overlapping antisense transcription locus with HOXC11. We identified HOTAIR-N as the dominant isoform that regulates the gene expression programs and networks for cell proliferation, survival, and death in cancer cells. The CpG island in the HOTAIR-N promoter was marked with epigenetic markers for active transcription. We identified a G-quadruplex (G4) motif rich region in the HOTAIR-N CpG island. Our findings indicate that G4s in HOTAIR-N CpG island is critical for expression of HOTAIR-N in cancer cells. Disruption of G4 may represent a novel therapeutic approach for cancer. The transcriptomes regulated by HOTAIR-N and Bloom in cancer cells as provided herein are important resources for the exploration of lncRNA, DNA helicases, and G4 in cancer.
