Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

Heylen, Elien; Verstraete, Paulien; Aerschot, Linde Van; Geeraerts, Shauni Lien; Venken, Tom; Timcheva, Kalina; Nittner, David; Verbeeck, Johan; Royaert, Jonathan; Gijbels, Marion J.J.; Uyttebroeck, Anne; Segers, Heidi; Lambrechts, Diether; Cools, Jan; Keersmaecker, Kim De; Kampen, Kim R.

doi:10.1038/s41416-023-02216-y

Cited by 7 publications

(5 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sertraline impairs disease progression in mice xenografted with human patient derived NKX2‐1 positive T‐ALL. Strikingly, an even stronger reduction in disease progression is obtained by combining sertraline with a serine/glycine free diet in these mice, further underscoring the dependency of NKX2‐1 cancer cells on serine/glycine synthesis (12).…”

Section: Ssp Hyperactivation In Acute Lymphoblastic Leukemia (All)mentioning

confidence: 87%

“…Moreover, RPL10 mutated cells are sensitive to the repurposed dual SHMT1/2 inhibitor sertraline, further confirming the role of RPL10 R98S as a driver of serine/glycine synthesis (11). Upregulation of PSPH, PSAT1 and SHMT1/2 expression also occurs in the NKX2-1 T-ALL subgroup (9,12), where the transcription factor NKX2-1 is ectopically expressed due to NKX2-1 rearrangements (13)(14)(15). NKX2-1 directly binds the PHGDH, PSAT1, PSPH and SHMT2 promoter and PSPH enhancer, inducing expression of these genes.…”

Section: Ssp Hyperactivation In Acute Lymphoblastic Leukemia (All)mentioning

confidence: 99%

“…Upregulation of PSPH , PSAT1 and SHMT1/2 expression also occurs in the NKX2‐1 T‐ALL subgroup (9,12), where the transcription factor NKX2‐1 is ectopically expressed due to NKX2‐1 rearrangements (13–15). NKX2‐1 directly binds the PHGDH , PSAT1 , PSPH and SHMT2 promoter and PSPH enhancer, inducing expression of these genes.…”

Section: Ssp Hyperactivation In Acute Lymphoblastic Leukemia (All)mentioning

confidence: 99%

See 2 more Smart Citations

Drivers of de novo Serine/Glycine synthesis in acute leukemia

2023

Self Cite

View full text Add to dashboard Cite

Cancer cells hijack metabolic pathways in order to provide themselves with building blocks to support their proliferation and survival. Upregulation and addiction to de novo serine/glycine synthesis is an example of metabolic rewiring in cancer cells whereby serine and glycine are synthesised via a side branch of glycolysis. In this review, we focus on upregulation of endogenous serine/glycine production in acute leukemia, namely T‐cell acute leukemia (T‐ALL) and acute myeloid leukemia (AML). Several genetic lesions directly driving the serine/glycine addiction in acute leukemia have been established. Additionally, indirect regulation of de novo serine/glycine synthesis is observed in acute leukemia.

show abstract

Section: Ssp Hyperactivation In Acute Lymphoblastic Leukemia (All)mentioning

confidence: 87%

Section: Ssp Hyperactivation In Acute Lymphoblastic Leukemia (All)mentioning

confidence: 99%

Section: Ssp Hyperactivation In Acute Lymphoblastic Leukemia (All)mentioning

confidence: 99%

See 1 more Smart Citation

Drivers of de novo Serine/Glycine synthesis in acute leukemia

2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, in the context of tumor microenvironment (TME) acidification, the export of lactate ions and H+ ions through hypoxia/HIF-1α-driven MCT4 enhances the acidity of the TME. This upregulates MMP-2 and MMP-9, leading to increased tissue-protein activity, EMT, and metastasis through augmented ROS formation [ 27 , 32 ]. The acidic pH, resulting from lactic acid accumulation, also impedes the release of inflammatory cytokines essential for helper T cell polarization and differentiation of inflammatory dendritic cells [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

SLC2A3 promotes tumor progression through lactic acid-promoted TGF-β signaling pathway in oral squamous cell carcinoma

Jiang,

Xu,

2024

PLoS ONE

View full text Add to dashboard Cite

Backgrounds Oral squamous cell carcinoma is a malignant tumor of the head and neck, and its molecular mechanism remains to be explored. Methods By analyzing the OSCC data from the TCGA database, we found that SLC2A3 is highly expressed in OSCC patients. The expression level of SLC2A3 was verified by RT-PCR and western blotting in OSCC cell lines. The function of SLC2A3 in OSCC cell lines and Lactic acid in SLC2A3-knockdown OSCC cells were detected by colony formation, CCK8, transwell, and wound healing assays. The effect of SLC2A3 on tumor growth and metastasis was tested in vivo. GSEA and Western blot were used to analyze and validate tumor phenotypes and signaling pathway molecules. Results We analyzed OSCC datasets in the TCGA database and found that SLC2A3 had abnormally high expression and was associated with poor prognosis. We also found that oral squamous cell carcinoma cells had increased proliferation, migration, invasion, EMT phenotype, and glycolysis due to SLC2A3 overexpression. Conversely, SLC2A3 knockdown had the opposite effect. Our in vivo experiments confirmed that SLC2A3 overexpression promoted tumor growth and metastasis while knockdown inhibited it. We also observed that high SLC2A3 expression led to EMT and the activation of the TGF-β signaling pathway, while knockdown inhibited it. Interestingly, exogenous lactic acid restored the EMT, proliferation, migration, and invasion abilities of oral cancer cells inhibited by knocking down SLC2A3. Conclusions Our study reveals that SLC2A3 expression was up-regulated in OSCC. SLC2A3 activates the TGF-β signaling pathway through lactic acid generated from glycolysis, thus regulating the biological behavior of OSCC.

show abstract

“…An increased contribution of the SSP was also shown to be mediated by the transcription factor Myc [ 66 ]. From its association with SSP enzyme expression and stimulatory effect of serine synthesis from labeled glucose, also transcription factor NKX2–1 was identified as an activator of the SSP in lung cancer cells [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells

Haitzmann,

Schindlmaier,

Frech

et al. 2024

Cancer Metab

View full text Add to dashboard Cite

Serine and glycine give rise to important building blocks in proliferating cells. Both amino acids are either synthesized de novo or taken up from the extracellular space. In lung cancer, serine synthesis gene expression is variable, yet, expression of the initial enzyme, phosphoglycerate dehydrogenase (PHGDH), was found to be associated with poor prognosis. While the contribution of de novo synthesis to serine pools has been shown to be enhanced by serine starvation, the impact of glucose deprivation, a commonly found condition in solid cancers is poorly understood. Here, we utilized a stable isotopic tracing approach to assess serine and glycine de novo synthesis and uptake in different lung cancer cell lines and normal bronchial epithelial cells in variable serine, glycine, and glucose conditions. Under low glucose supplementation (0.2 mM, 3–5% of normal plasma levels), serine de novo synthesis was maintained or even activated. As previously reported, also gluconeogenesis supplied carbons from glutamine to serine and glycine under these conditions. Unexpectedly, low glucose treatment consistently enhanced serine to glycine conversion, along with an up-regulation of the mitochondrial one-carbon metabolism enzymes, serine hydroxymethyltransferase (SHMT2) and methylenetetrahydrofolate dehydrogenase (MTHFD2). The relative contribution of de novo synthesis greatly increased in low serine/glycine conditions. In bronchial epithelial cells, adaptations occurred in a similar fashion as in cancer cells, but serine synthesis and serine to glycine conversion, as assessed by label enrichments and gene expression levels, were generally lower than in (PHGDH positive) cancer cells. In summary, we found a variable contribution of glucose or non-glucose carbon sources to serine and glycine and a high adaptability of the downstream one-carbon metabolism pathway to variable glucose supply.

show abstract

Transcription factor NKX2–1 drives serine and glycine synthesis addiction in cancer

Cited by 7 publications

References 71 publications

Drivers of de novo Serine/Glycine synthesis in acute leukemia

Drivers of de novo Serine/Glycine synthesis in acute leukemia

SLC2A3 promotes tumor progression through lactic acid-promoted TGF-β signaling pathway in oral squamous cell carcinoma

Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells

Contact Info

Product

Resources

About