title: Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2.
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.
authors.affiliation: Pfizer Oncology Research Unit, San Diego, CA, USA stephen.dann@pfizer.com.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Dann
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ryskin
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Barsotti
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Golas
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Shi
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Miranda
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hosselet
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Luanna
authors.initials: L
authors.lastname: Lemon
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Celgene, Summit, NJ, USA.
authors.forename: Maha
authors.initials: M
authors.lastname: Karnoub
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Myers
authors.affiliation: Pfizer Oncology Research Unit, San Diego, CA, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Garza
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Maximillian T
authors.initials: MT
authors.lastname: Follettie
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Geles
authors.affiliation: Celgene, Summit, NJ, USA.
authors.forename: Anke
authors.initials: A
authors.lastname: Klippel
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rollins
authors.affiliation: Pfizer Oncology Research Unit, San Diego, CA, USA.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D027283:Large Neutral Amino Acid-Transporter 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: SLC7A5; S‐adenosylmethionine; cancer metabolism; methionine cycle