Premium
Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH 2
Author(s) -
Dann Stephen G,
Ryskin Michael,
Barsotti Anthony M,
Golas Jonathon,
Shi Celine,
Miranda Miriam,
Hosselet Christine,
Lemon Luanna,
Lucas Judy,
Karnoub Maha,
Wang Fang,
Myers Jeremy S,
Garza Scott J,
Follettie Maximillian T,
Geles Kenneth G,
Klippel Anke,
Rollins Robert A,
Fantin Valeria R
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201488166
Subject(s) - gene knockdown , biology , ezh2 , amino acid , psychological repression , methyltransferase , prc2 , methionine , biochemistry , cancer research , microbiology and biotechnology , methylation , gene expression , gene
Lat1 ( SLC 7A5) 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 ( PRC 2)‐specific EZH 2. Cell populations sorted for surface Lat1 exhibit activated EZH 2, enrichment for Met ‐cycle intermediates, and aggressive tumor growth in mice. In agreement, EZH 2 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. EZH 2 knockdown or small‐molecule inhibition leads to de‐repression of RXR α resulting in reduced Lat1 expression. Our results describe a Lat1‐ EZH 2 positive feedback loop illustrated by AA depletion or Lat1 knockdown resulting in SAM reduction and concomitant reduction in EZH 2 activity. sh RNA ‐mediated knockdown of Lat1 results in tumor growth inhibition and points to Lat1 as a potential therapeutic target.