title: Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers.
abstract: Sex hormones and their receptors play critical roles in the development and progression of the breast and prostate cancers. Here we report that a novel type of transfer RNA (tRNA)-derived small RNA, termed Sex HOrmone-dependent TRNA-derived RNAs (SHOT-RNAs), are specifically and abundantly expressed in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer cell lines. SHOT-RNAs are not abundantly present in ER(-) breast cancer, AR(-) prostate cancer, or other examined cancer cell lines from other tissues. ER-dependent accumulation of SHOT-RNAs is not limited to a cell culture system, but it also occurs in luminal-type breast cancer patient tissues. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated anticodon cleavage, which is promoted by sex hormones and their receptors. Resultant 5'- and 3'-SHOT-RNAs, corresponding to 5'- and 3'-tRNA halves, bear a cyclic phosphate (cP) and an amino acid at the 3'-end, respectively. By devising a "cP-RNA-seq" method that is able to exclusively amplify and sequence cP-containing RNAs, we identified the complete repertoire of 5'-SHOT-RNAs. Furthermore, 5'-SHOT-RNA, but not 3'-SHOT-RNA, has significant functional involvement in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis of hormone-dependent cancers and implicate SHOT-RNAs as potential candidates for biomarkers and therapeutic targets.
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Shozo
authors.initials: S
authors.lastname: Honda
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Phillipe
authors.initials: P
authors.lastname: Loher
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Megumi
authors.initials: M
authors.lastname: Shigematsu
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Juan P
authors.initials: JP
authors.lastname: Palazzo
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Human Genetics, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Isidore
authors.initials: I
authors.lastname: Rigoutsos
authors.affiliation: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107; Yohei.Kirino@jefferson.edu.
authors.forename: Yohei
authors.identifier: http://orcid.org/0000-0001-5232-4742
authors.initials: Y
authors.lastname: Kirino
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D012831:Bombyx; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D010710:Phosphates; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012343:RNA, Transfer / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D000596:Amino Acids; D012739:Gonadal Steroid Hormones; D010710:Phosphates; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: breast cancer; prostate cancer; sex hormone; tRNA; tRNA half