Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers

Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):E3816-25. doi: 10.1073/pnas.1510077112. Epub 2015 Jun 29.


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.

Keywords: breast cancer; prostate cancer; sex hormone; tRNA; tRNA half.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Animals
  • Base Sequence
  • Bombyx
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Epithelial Cells / metabolism
  • Female
  • Gene Knockdown Techniques
  • Gonadal Steroid Hormones / metabolism*
  • Humans
  • Hydroxylation
  • Male
  • Models, Biological
  • Molecular Sequence Data
  • Phosphates
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • RNA, Transfer / chemistry
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Androgen / metabolism
  • Receptors, Estrogen / metabolism
  • Ribonuclease, Pancreatic / metabolism
  • Sequence Analysis, RNA


  • Amino Acids
  • Gonadal Steroid Hormones
  • Phosphates
  • Receptors, Androgen
  • Receptors, Estrogen
  • RNA, Transfer
  • angiogenin
  • Ribonuclease, Pancreatic

Associated data

  • SRA/SRX1060214