Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA

Yasuyuki Hosono; Yashar S Niknafs; John R Prensner; Matthew K Iyer; Saravana M Dhanasekaran; Rohit Mehra; Sethuramasundaram Pitchiaya; Jean Tien; June Escara-Wilke; Anton Poliakov; Shih-Chun Chu; Sahal Saleh; Keerthana Sankar; Fengyun Su; Shuling Guo; Yuanyuan Qiao; Susan M Freier; Huynh-Hoa Bui; Xuhong Cao; Rohit Malik; Timothy M Johnson; David G Beer; Felix Y Feng; Weibin Zhou; Arul M Chinnaiyan

doi:10.1016/j.cell.2017.11.040

Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA

Cell. 2017 Dec 14;171(7):1559-1572.e20. doi: 10.1016/j.cell.2017.11.040.

Authors

Yasuyuki Hosono¹, Yashar S Niknafs², John R Prensner³, Matthew K Iyer⁴, Saravana M Dhanasekaran⁵, Rohit Mehra⁵, Sethuramasundaram Pitchiaya¹, Jean Tien¹, June Escara-Wilke⁶, Anton Poliakov¹, Shih-Chun Chu¹, Sahal Saleh¹, Keerthana Sankar¹, Fengyun Su¹, Shuling Guo⁷, Yuanyuan Qiao¹, Susan M Freier⁷, Huynh-Hoa Bui⁷, Xuhong Cao¹, Rohit Malik⁵, Timothy M Johnson⁸, David G Beer⁹, Felix Y Feng¹⁰, Weibin Zhou¹¹, Arul M Chinnaiyan¹²

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
² Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
³ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
⁴ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁵ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Urology, University of Michigan, Ann Arbor, MI, USA.
⁷ Ionis Pharmaceuticals, Carlsbad, CA, USA.
⁸ Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁹ Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
¹² Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.

Abstract

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.

Keywords: IGF2BP1; RNA; RNA-seq; cancer; conservation; fertility; iCLIP; lncRNA; zebrafish.

MeSH terms

Animals
Cell Line, Tumor
Disease Models, Animal*
Gene Knockout Techniques
Humans
Male
Melanoma / metabolism*
Mice
RNA, Long Noncoding / metabolism*
RNA-Binding Proteins / metabolism
Testis / metabolism
Zebrafish*

Substances

IGF2BP1 protein, human
RNA, Long Noncoding
RNA-Binding Proteins

Abstract

MeSH terms

Substances

Grants and funding