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 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 six 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 four genes that are overexpressed in amplicon-positive RMS. Among these genes, only SHMT2 was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in ampliconpositive 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 demonstrated that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

Anaplastic Thyroid Cancer Cells Upregulate Mitochondrial One-Carbon Metabolism To Meet Purine Demand, Eliciting A Critical Targetable Vulnerability

“…In particular, SHIN1 has been synthesized as an inhibitor of SHMT1/2 [19], and DS18561882 as an inhibitor of MTHFD2 [20]. These compounds have recently been shown to reduce cell proliferation in lymphoma [19], rhabdomyosarcoma [21], bladder [22] and lung cancer [23,24] cell lines.…”

Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2

“…The SHMT2 enzyme is usually highly expressed in cancers, and SHMT2 deficiency leads to mitochondrial respiration defects ( Lucas et al., 2018 ; Minton et al., 2018 ; Morscher et al., 2018 ; Tani et al., 2018 , 2019 ), which makes SHMT2 a promising target for cancer treatment ( Ding et al., 2013 ; Kim et al., 2015 ; Liu et al., 2021 ; Nguyen et al., 2021 ; Wei et al., 2018 ; Yang et al., 2018 ). The mitochondrial respiration system is a well-known machine that generates ATP in mammalian cells.…”

EGFR protein editing by serine hydroxymethyl transferase SHMT2

“…The widespread overexpression of SHMT2 has been observed in various types of cancer, and an overall higher level of SHMT2 expression has been seen in lung squamous cell carcinoma compared to lung adenocarcinoma, according to the KEGG database (Extended Data Fig. 6e-g) 47 . This might elucidate why EGFR-targeted therapy with TKIs is less effective in lung squamous carcinoma than in lung adenocarcinoma 48 .…”