Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis

Cell Death Dis. 2016 Jun 9;7(6):e2262. doi: 10.1038/cddis.2016.168.

Abstract

BC200 is a long non-coding RNA (lncRNA) that has been implicated in the regulation of protein synthesis, yet whether dysregulation of BC200 contributes to the pathogenesis of human diseases remains elusive. In this study, we show that BC200 is upregulated in breast cancer; among breast tumor specimens there is a higher level of BC200 in estrogen receptor (ER) positive than in ER-negative tumors. Further experiments show that activation of estrogen signaling induces expression of BC200. To determine the significance of ER-regulated BC200 expression, we knockout (KO) BC200 by CRISPR/Cas9. BC200 KO suppresses tumor cell growth in vitro and in vivo by expression of the pro-apoptotic Bcl-xS isoform. Mechanistically, BC200 contains a 17-nucleotide sequence complementary to Bcl-x pre-mRNA, which may facilitate its binding to Bcl-x pre-mRNA and recruitment of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a known splicing factor. Consequently, hnRNP A2/B1 interferes with association of Bcl-x pre-mRNA with the Bcl-xS-promoting factor Sam68, leading to a blockade of Bcl-xS expression. Together, these results suggest that BC200 plays an oncogenic role in breast cancer. Thus, BC200 may serve as a prognostic marker and possible target for attenuating deregulated cell proliferation in estrogen-dependent breast cancer.

Publication types

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

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Estrogens / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockout Techniques
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • Humans
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Precursors / metabolism
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • bcl-X Protein / genetics*
  • bcl-X Protein / metabolism

Substances

  • Estrogens
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Protein Isoforms
  • RNA Precursors
  • RNA, Long Noncoding
  • RNA, Messenger
  • bcl-X Protein
  • long non-coding RNA BC200, human