Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification
Thanh H. Nguyen, … , Wenyue Sun, Frederic G. Barr
Thanh H. Nguyen, … , Wenyue Sun, Frederic G. Barr
Published June 24, 2021
Citation Information: J Clin Invest. 2021;131(15):e138022. https://doi.org/10.1172/JCI138022.
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Research Article Cell biology Oncology

Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification

Abstract

The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and 6 other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes 4 genes that are overexpressed in amplicon-positive RMS. Among these genes, only serine hydroxymethyltransferase 2 (SHMT2) was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in amplicon-positive RMS cells suppressed growth, transformation, and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrates that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

Authors

Thanh H. Nguyen, Prasantha L. Vemu, Gregory E. Hoy, Salah Boudjadi, Bishwanath Chatterjee, Jack F. Shern, Javed Khan, Wenyue Sun, Frederic G. Barr

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Figure 3

Distribution of 12q13-q14 amplicons across cancer types and expression in FP RMS.

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Distribution of 12q13-q14 amplicons across cancer types and expression i...
(A) Summary of the sizes, distributions, and expression consequences of 12q13-q14 amplicons in each tumor type. The large colored rectangles correspond to the high-confidence regions of amplification, which are the genomic regions that are significantly and highly amplified in amplicon-positive samples, as described in Figure 2. Genes that are significantly and highly overexpressed in amplicon-positive samples were determined as described in Figure 3B and are shown as small colored rectangles. Gray bars indicate that there was insufficient RNA-Seq data for the corresponding genes. (B) Expression levels of genes from the 12q13-q14 region in FP RMS tumors. Genes in and around the 12q13-q14 amplified region were analyzed for significant differences in gene-expression levels between amplicon-positive (gray) and amplicon-negative (white) samples. Genes that had Bonferroni’s corrected P values ≤ 0.05 and fold changes ≥ 2.0 are indicated with black rectangles.