Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2

EMBO J. 2015 Jul 2;34(13):1773-85. doi: 10.15252/embj.201488166. Epub 2015 May 15.

Abstract

Lat1 (SLC7A5) is an amino acid transporter often required for tumor cell import of essential amino acids (AA) including Methionine (Met). Met is the obligate precursor of S-adenosylmethionine (SAM), the methyl donor utilized by all methyltransferases including the polycomb repressor complex (PRC2)-specific EZH2. Cell populations sorted for surface Lat1 exhibit activated EZH2, enrichment for Met-cycle intermediates, and aggressive tumor growth in mice. In agreement, EZH2 and Lat1 expression are co-regulated in models of cancer cell differentiation and co-expression is observed at the invasive front of human lung tumors. EZH2 knockdown or small-molecule inhibition leads to de-repression of RXRα resulting in reduced Lat1 expression. Our results describe a Lat1-EZH2 positive feedback loop illustrated by AA depletion or Lat1 knockdown resulting in SAM reduction and concomitant reduction in EZH2 activity. shRNA-mediated knockdown of Lat1 results in tumor growth inhibition and points to Lat1 as a potential therapeutic target.

Keywords: SLC7A5; S‐adenosylmethionine; cancer metabolism; methionine cycle.

MeSH terms

  • Amino Acids / metabolism*
  • Animals
  • Biological Transport / genetics
  • Cell Proliferation / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenesis, Genetic / physiology*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Large Neutral Amino Acid-Transporter 1 / physiology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Polycomb Repressive Complex 2 / physiology*
  • Tumor Cells, Cultured

Substances

  • Amino Acids
  • Large Neutral Amino Acid-Transporter 1
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2