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

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. sh RNA-mediated knockdown of Lat1 results in tumor growth inhibition and points to Lat1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]