The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing

Sara Parsa, Ana Ortega-Molina, Hsia Yuan Ying, Man Jiang, Matt Teater, Jiahui Wang, Chunying Zhao, Ed Reznik, Joyce P. Pasion, David Kuo, Prathibha Mohan, Shenqiu Wang, Jeannie M. Camarillo, Paul M. Thomas, Neeraj Jain, Javier Garcia-Bermudez, Byoung kyu Cho, Wayne Tam, Neil L. Kelleher, Nicholas SocciAhmet Dogan, Elisa De Stanchina, Giovanni Ciriello, Michael R. Green, Sheng Li, Kivanc Birsoy, Ari M. Melnick, Hans Guido Wendel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)653-664
Number of pages12
JournalNature Cancer
Volume1
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

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