Nature cancer · 2020
The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Parsa Sara, Ortega-Molina Ana, Ying Hsia-Yuan, Jiang Man, Teater Matt, Wang Jiahui, Zhao Chunying, Reznik Ed, Pasion Joyce P, Kuo David, Mohan Prathibha, Wang Shenqiu, Camarillo Jeannie M, Thomas Paul M, Jain Neeraj, Garcia-Bermudez Javier, Cho Byoung-Kyu, Tam Wayne, Kelleher Neil L, Socci Nicholas, Dogan Ahmet, De Stanchina Elisa, Ciriello Giovanni, Green Michael R, Li Sheng, Birsoy Kivanc, Melnick Ari M, Wendel Hans-Guido
Аннотация
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.