SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation

Sci Rep. 2017 Mar 30:7:45361. doi: 10.1038/srep45361.

Abstract

The serum- and glucocorticoid-regulated kinase (SGK1) controls cell transformation and tumor progression. SGK1 affects mitotic stability by regulating the expression of RANBP1/RAN. Here, we demonstrate that SGK1 fluctuations indirectly modify the maturation of pre-miRNAs, by modulating the equilibrium of the RAN/RANBP1/RANGAP1 axis, the main regulator of nucleo-cytoplasmic transport. The levels of pre-miRNAs and mature miRNAs were assessed by qRT-PCR, in total extracts and after differential nuclear/cytoplasmic extraction. RANBP1 expression is the limiting step in the regulation of SGK1-SP1 dependent nuclear export. These results were validated in unrelated tumor models and primary human fibroblasts and corroborated in tumor-engrafted nude mice. The levels of pri-miRNAs, DROSHA, DICER and the compartmental distribution of XPO5 were documented. Experiments using RANGTP conformational antibodies confirmed that SGK1, through RANBP1, decreases the level of the GTP-bound state of RAN. This novel mechanism may play a role in the epigenomic regulation of cell physiology and fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism*
  • Epigenesis, Genetic
  • HEK293 Cells
  • Humans
  • Immediate-Early Proteins / metabolism*
  • Mice
  • MicroRNAs / metabolism*
  • Neoplasm Transplantation
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Sp1 Transcription Factor / metabolism*
  • ran GTP-Binding Protein / metabolism*

Substances

  • Immediate-Early Proteins
  • MicroRNAs
  • Nuclear Proteins
  • RAN protein, human
  • Sp1 Transcription Factor
  • SP1 protein, human
  • ran-binding protein 1
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • ran GTP-Binding Protein