Open AccessThe serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing
Author(s) -
Sara Parsa,
Ana Ortega-Molina,
HsiaYuan Ying,
Man Jiang,
Matt Teater,
Jiahui Wang,
Chunli Zhao,
Ed Reznik,
Joyce Pasion,
David Kuo,
Prathibha Mohan,
Shenqiu Wang,
Jeannie M. Camarillo,
Paul M. Thomas,
Neeraj Jain,
Javier GarcíaBermúdez,
Byoung-kyu Cho,
Wayne Tam,
Neil L. Kelleher,
Nicholas D. Socci,
Ahmet Doğan,
Elisa de Stanchina,
Giovanni Ciriello,
Michael R. Green,
Sheng Li,
Kıvanç Birsoy,
Ari Melnick,
Hans-Guido Wendel
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0080-0
Subject(s) - serine hydroxymethyltransferase , gene silencing , epigenetics , biology , dna methylation , cancer research , ubiquitin ligase , lymphoma , genetics , gene , serine , gene expression , ubiquitin , immunology , phosphorylation
Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S -adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.