Prognostic and therapeutic value of mitochondrial serine hydroxyl-methyltransferase 2 as a breast cancer biomarker

Abstract

Mitochondrial serine hydroxylmethyltransferase 2 (SHMT2) is a key enzyme in the serine/glycine synthesis pathway. SHMT2 has been implicated as a critical component for tumor cell survival. The aim of the present study was to evaluate the prognostic value and efficiency of SHMT2 as a biomarker in patients with breast cancer. Individual and pooled survival analyses were performed on five independent breast cancer microarray datasets. Gene signatures enriched by SHMT2 were also analyzed in these datasets. SHMT2 protein expression was detected using immunohistochemistry (IHC) assay in 128 breast cancer cases. Gene set enrichment analysis revealed that SHMT2 was significantly associated with gene signatures of mitochondrial module, cancer invasion, metastasis and poor survival among breast cancer patients (p<0.05). The clinical relevance of SHMT2 was validated on IHC data. The mitochondrial localization of SHMT2 protein was visualized on IHC staining. Independent and pooled analysis confirmed that SHMT2 expression was associated with breast cancer tumor aggressiveness (TNM staging and Elson grade) in a dose-dependent manner (p<0.05). The prognostic performance of SHMT2 mRNA was comparable to other gene signatures and proved superior to TNM staging. Further analysis results indicated that SHMT2 had better prognostic value for estrogen receptor (ER)-negative breast cancer patients, compared to ER-positive patients. In cases involving stage IIb breast cancer, chemotherapy significantly extended survival time among patients with high SHMT2 expression. These results indicate that SHMT2 may be a valuable prognostic biomarker in ER-negative breast cancer cases. Furthermore, SHMT2 may be a potential target for breast cancer treatment and drug discovery.

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

“…Similarly, many other mitochondria-resident APE1-PPIs were found to be commonly up-regulated in the analyzed datasets. Among these, it is worth mentioning: (i) SHMT2 (serine hydroxymethyltransferase), that mainly localizes to the matrix, nucleoid and inner membranes, and is known to be targeted by c-myc for cell survival, with various studies confirming its bad prognostic power in different cancer types [87][88][89][90][91] ; (ii) pro-apoptotic protein SLC25A6 (mitochondrial ADP/ATP carrier-3, AAC3) 92,93 ; (iii) ROS regulating respiratory complex III protein UQCRC2 (ubiquinol-cytochrome c reductase complex core protein 2) 94 ; (iv) respiratory complex II protein SDHB (succinate dehydrogenase B) 95 ; v) fatty acid βoxidation proteins ETFA (electron transfer flavoprotein subunit alpha) 96,97 and ACAA2 (acetyl-CoA acyltransferase 2) 98 ; vi) bad prognostic multifunctional LGALS3 (galectin-3) protein 99 ; (vii) autoimmunity protein HARS (histidyl-tRNA synthetase) 100 ; (viii) oxidative damage control protein IDH1 (isocitrate dehydrogenase 1) 101 . Additional matrix proteins were found being up-regulated in LIHC and LUAD, while down-regulated in PAAD; they included fatty acid β-oxidation proteins ECHS1 (enoyl coenzyme A hydratase short chain 1) 102 and ETFB (electron transfer flavoprotein subunit beta) 103 , multifunctional protein 17β-HSD10 (17β-hydroxysteroid dehydrogenase type 10, encoded by HSD17B10) 104 and mitochondrial protein processor PMPCA (mitochondrial-processing peptidase subunit alpha) 105 .…”

Overexpression of mitochondrial serine hydroxyl-methyltransferase 2 is associated with poor prognosis and promotes cell proliferation and invasion in gliomas

“… 7 Accumulating studies have reported that abnormal expression of SHMT2 may play an important role in tumorigenesis and tumor progression of various human malignancies. 8 – 11 Especially, Kim et al 12 indicated that SHMT2 was elevated in a subset of glioma cells and promoted changes in metabolism that allowed cells to survive in an ischemic tumor microenvironment. However, its clinical relevance in human gliomas remains unclear.…”

Silencing SHMT2&nbsp;Inhibits the Progression of Oral Squamous Cell Carcinoma Through Cell Cycle Regulation

“…SHMT2 is a key enzyme in one-carbon metabolism, and is responsible for the conversion of serine to glycine. Several studies have found that SHMT2 is elevated in a range of tumors, and high levels of SHMT2 are associated with poor prognosis in patients [17,[28][29][30]. One study found that SHMT2 contributes to cancer cell survival in the harsh tumor microenvironment, which relies on glycine clearance [20].…”

“…As the hub of serine catabolism and single carbon metabolism, SHMT2 plays a regulatory role, in which small molecular metabolites control cell proliferation [16]. SHMT2 has been reported to be up-regulated in a variety of cancer types such as breast cancer, hepatocellular carcinoma, and lung cancer, and elevated SHMT2 is signi cantly associated with poor prognosis of patients [17][18][19]. In glioma cells, SHMT2 has been shown to contribute to cell proliferation in ischemic and hypoxia tumor microenvironments [20].…”