Table 1.
The reprogramming of serine, glycine and one-carbon pathway across cancer types.
| Study | Enzyme(s) | Expression up or down | Cancer Type(s) | Regulated by | Function/Phenotype/Major conclusion |
|---|---|---|---|---|---|
| (Nilsson et al., 2012) | SHMT1, SHMT2 | Up | Acute myeloid leukemia (murine) | λ-MYC | Dispensable for tumor initiation and progression |
| (Pikman et al., 2016) | MTHFD2 | Up | Acute myeloid leukemia (human, murine) | MYC | Knockdown decreased proliferation, induced differentiation, impaired colony formation, and suppressed TCA cycle |
| (Leivonen et al., 2011) | SHMT2 | Up | Breast (human) | miR-193b | Repressed by miR-193b to restrain ER+ growth |
| (Jain et al., 2012) | SHMT1, SHMT2 | N/A | Breast (human) | N/A | SHMT2 but not SHMT1 correlates with mortality |
| (Lehtinen et al., 2013) | MTHFD2 | Up | Breast (human) | N/A | Knockdown reduced vimentin expression, migration, invasion, and fraction of CD44hi cells |
| (Ye et al., 2014a) | SHMT2 | Up | Breast, Neuroblastoma (human) | HIF1α, N-Myc | Induced by hypoxia to maintain redox balance through NADPH generation |
| (Yin, 2015) | SHMT2 | Up | Breast (human) | N/A | Expression correlated with tumor grade |
| (Samanta et al., 2016) | SHMT2 | Up | Breast (human) | HIF1α, HIF2α | Induced by hypoxia and mammosphere culture |
| (Bernhardt et al., 2017) | SHMT2 | Up | Breast (human) | N/A | High expression correlates with poor patient survival |
| (Chen et al., 2019a) | SHMT2 | Up | Breast (human) | EIF2A, ATF4 | Involvement in integrated stress response following paclitaxel treatment |
| (Li et al., 2020) | SHMT2, MTHFD2, MTHFD1L | Up | Breast (human) | MYC (for MTHFD2 and MTHFD1L) | Upregulated in aggressive, highly metastatic subclones of triple-negative breast cancer cells; SHMT2 knockdown reduced metastatic growth |
| (Miyo et al., 2017) | SHMT2, MTHFD2, ALDH1L2 | Up | Colorectal (human) | N/A | High expression of all 3 enzymes correlated with poor patient survival |
| (Agarwal et al., 2019) | MTHFD1L | Up | Colorectal (human) | N/A | Supports proliferation, colony formation, invasion and migration |
| (Ju et al., 2019) | MTHFD2 | Up | Colorectal (human) | c-Myc | Knockdown disturbed redox balance and accelerated cell death under hypoxia and anchorage independent growth |
| (Tanner et al., 2017) | SHMT1, SHMT2 | Up | Ewing sarcoma (human) | EWS/FLI | High expression correlated with poor patient survival |
| (Kim et al., 2015) | GLDC, SHMT2 | Up | Glioma (human) | N/A | SHMT2 suppresses PKM2 activity and decreases oxygen consumption; GLDC clears excess glycine, providing survival benefit under hypoxia |
| (Wang et al., 2017) | SHMT2 | Up | Glioma (human) | N/A | Expression correlated with tumor grade |
| (Woo et al., 2016) | SHMT2, GLDC | Up | Hepatocellular carcinoma (human) | N/A | SHMT2 is necessary but not sufficient for liver tumorigenesis |
| (Wu et al., 2016b) | SHMT2 | Up | Hepatocellular carcinoma (human) | miR-615-5p | Promotes proliferation and migration |
| (Paone et al., 2014) | SHMT1, SHMT2 | Up | Lung cancer (human) | N/A | SHMT1 knockdown leads to misincorporation of uracil in genomic DNA, cell cycle arrest, apoptosis |
| (Wu et al., 2016a) | SHMT1 | Up | Lung adenocarcinoma (human) | miR-198 | Knockdown leads to less proliferation, increased apoptosis, cell-cycle arrest |
| (Zhang et al., 2012) | GLDC | Up | Non-small cell lung cancer (human) | N/A | Necessary and sufficient for lung tumorigenicity |
| (DeNicola et al., 2015) | SHMT2 | Up | Non-small cell lung cancer (human) | NRF2, ATF4 | Links serine biosynthesis to nucleotide and glutathione synthesis |
| (Piskounova et al., 2015) | ALDH1L2 | Up | Melanoma (human, murine) | N/A | Necessary for NADPH-mediate ROS suppression in metastatic cells |
| (Kottakis et al., 2016) | GLDC, SHMT1, SHMT2, | Up | Pancreatic adenocarcinoma (murine) | LKB1, mTOR | Links serine biosynthesis to DNA methylation |
| (Reina-Campos et al., 2019) | MTHFD2 | Up | Neuroendocrine prostate cancer (murine) | PKCλ/ι, mTOR, ATF4 | Links serine biosynthesis to DNA methylation and neuroendocrine progenitor cell differentiation |
| (Lin et al., 2018) | MTHFD2 | Up | Renal cell carcinoma | N/A | Knockdown decreased cell proliferation, invasion, and migration |
| (Green et al., 2019) | MTHFD2 | Up | Renal cell carcinoma | HIF-2α | Forms positive feedforward loop with HIF-2α to control RNA methylation and reprogram metabolism |
| (Nilsson et al., 2014) | MTHFD2 | Up | Pan-cancer (human) | N/A | Consistently elevated in many cancers, correlates with poor survival in breast cancer, knockdown causes cell death in most cancer cell lines |