Oncotarget

Research Papers:

Induction of serine hydroxymethyltransferase 2 promotes tumorigenesis and metastasis in neuroblastoma

Rachael A. Clark, Jingbo Qiao, Jillian C. Jacobson and Dai H. Chung _

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Abstract

Rachael A. Clark1, Jingbo Qiao1, Jillian C. Jacobson1 and Dai H. Chung1,2

1 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75234, USA

2 Department of Surgery, Children’s Health, Dallas, TX 75234, USA

Correspondence to:

Dai H. Chung, email: dai.chung@utsouthwestern.edu

Keywords: neuroblastoma; serine hydroxymethyltransferase 2 (SHMT2); tumorigenesis; serine metabolism; one-carbon metabolism

Received: August 25, 2021     Accepted: December 08, 2021     Published: January 06, 2022

Copyright: © 2022 Clark et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

High-risk neuroblastoma (NB) remains an extremely difficult subgroup to cure and is associated with MYCN amplification. Serine hydroxymethyltransferase 2 (SHMT2) regulates serine metabolism in a myc-dependent manner; it is upregulated in several cancers and is associated with tumor aggressiveness. Akt-2, an important regulator of MYCN via the PI3K/Akt pathway, induces metastatic potential in NB. The association between SHMT2 and PI3K/Akt in hepatocyte regeneration has been well established but its mechanistic interaction in cancer has yet to be clearly elucidated. Herein, we evaluated the exact role of SHMT2 on the PI3K/Akt pathway, in addition to NB tumorigenesis and metastatic potential in vitro. SHMT2 gene expression and overall survival (OS) were assessed. Two human NB cell lines were examined. SHMT2 silencing and overexpression were performed. The downstream effects were analyzed with immunoblotting, RT-qPCR and functional assays were performed. We found SHMT2 gene expression is associated with decreased OS and MYCN amplification. SHMT2 protein and mRNA expression are increased in MYCN-amplified cells. SHMT2 expression has a direct interaction with Akt-2 and MYCN. Induction of SHMT2 increased cellular proliferation, colony formation and cellular migration and SHMT2 expression was increased in metastatic NB cells. We conclude that SHMT2 regulates N-Myc via phosphorylation of Akt-2 and plays an important role in NB tumorigenesis by contributing to cell growth, migration, colony formation and metastasis in vitro.


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