Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours

Nat Commun. 2018 Nov 5;9(1):4624. doi: 10.1038/s41467-018-06853-3.

Abstract

Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cabergoline / pharmacology
  • Carcinogenesis
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Progression
  • Down-Regulation
  • Female
  • HEK293 Cells
  • Heterografts
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / drug effects*
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mice
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Pituitary Neoplasms / drug therapy
  • Pituitary Neoplasms / metabolism*
  • RNA, Long Noncoding / antagonists & inhibitors*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Up-Regulation

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • H19 long non-coding RNA
  • Phosphoproteins
  • RNA, Long Noncoding
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Cabergoline