PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress

Yoon, Bo Kyung; Kim, Hyeonhui; Oh, Tae Gyu; Oh, Sunhwa; Jo, Sugyeong; Kim, Min Ki; Chun, Kyu-Hye; Hwang, Nahee; Lee, Suji; Jin, Seok Min; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Kim, Jae-Woo; Kim, Hyun Kyung; Evans, Ronald M.; Cheong, Jae‐Ho; Fang, Sungsoon

doi:10.1073/pnas.2217826120

Cited by 10 publications

(5 citation statements)

References 49 publications

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“…However, glutamine deprivation and BPTES decreased cellular glutamate level, suggesting that these two approaches are interchangeable in the case of glutaminolysis impairment (Fig. 2A ) [ 30 , 31 ]. Glutamine metabolism inhibition with glutamine deprivation or BPTES markedly reduced cell growth and the number of colonies stained with crystal violet in 8505 C (Fig.…”

Section: Resultsmentioning

confidence: 99%

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

Hwang,

Yun,

Jeong

et al. 2023

Cell Death Dis

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Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors with an extremely poor prognosis. Based on the several biological features related to glutamine metabolism in ATC, we hypothesized glutaminolysis inhibition induces cell death in ATC cells. However, glutamine metabolism inhibition triggered cell growth arrest independent of cell death in ATC, suggesting that other signaling pathways avoid glutamine metabolism inhibition-induced stress exist. To investigate the functional mechanism against glutamine metabolism inhibition, we conducted mRNA and ATAC-Sequencing data analysis and found that glutamine deprivation increased ATF4-mediated one-carbon metabolism. When we inhibited PHGDH, the first rate-limiting enzyme for one-carbon metabolism, cell growth arrest was promoted upon glutamine metabolism inhibition by accumulating intracellular ROS. We next observed that the co-inhibition of glutamine and one-carbon metabolism could augment the anticancer effects of drugs used in patients with ATC. Finally, single-cell RNA sequencing analysis revealed that one-carbon metabolism was strengthened through the evolutionary process from PTC to ATC. Collectively, our data demonstrate that one-carbon metabolism has a potential role of modulation of cell fate in metabolic stress and can be a therapeutic target for enhancing antitumor effects in ATC.

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Section: Resultsmentioning

confidence: 99%

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

Hwang,

Yun,

Jeong

et al. 2023

Cell Death Dis

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“…SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type GC is the most aggressive subtype with no targeted therapies 22 . It is of note that progression of both SEM-type and non-SEM-type GC cells was remarkably suppressed by KH12 (Figure 5C and S6).…”

Section: Discussionmentioning

confidence: 99%

Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer

Hwang,

Bae,

Jhe

et al. 2024

Preprint

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Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancer types, either dependent or independent of its m6A methyl transferase activity. We have designed proteolysis-targeting chimeras (PROTACs) targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes more than 80% degradation of METTL3 with a half-maximal degradation concentration (DC50) of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 reverses differentiation and possesses anti proliferative effects surpassing the reported inhibitors in MOLM-13 cells. Furthermore, KH12 significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effect of KH12 was further confirmed in patient-derived organoids (PDOs). This study highlights the therapeutic potential of targeted degradation of epitranscriptomic writer METTL3 as an anti-cancer strategy.

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“…Yoon et al observed an increase in glutaminase and resistance to glutaminolysis inhibition in chemotherapy-resistant GC patients. This type of GC improves glucose metabolism as a survival strategy under conditions of starvation, highlighting intricate crosstalk between metabolic pathways [42].…”

Section: Discussionmentioning

confidence: 99%

Development of a Comprehensive Gene Signature Linking Hypoxia, Glycolysis, Lactylation, and Metabolomic Insights in Gastric Cancer through the Integration of Bulk and Single-Cell RNA-Seq Data

Zhang,

Li,

Chen

2023

Biomedicines

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Background: Hypoxia and anaerobic glycolysis are cancer hallmarks and sources of the metabolite lactate. Intriguingly, lactate-induced protein lactylation is considered a novel epigenetic mechanism that predisposes cells toward a malignant state. However, the significance of comprehensive hypoxia–glycolysis–lactylation-related genes (HGLRGs) in cancer is unclear. We aimed to construct a model centered around HGLRGs for predicting survival, metabolic features, drug responsiveness, and immune response in gastric cancer. Methods: The integration of bulk and single-cell RNA-Seq data was achieved using data obtained from the TCGA and GEO databases to analyze HGLRG expression patterns. A HGLRG risk-score model was developed based on univariate Cox regression and a LASSO-Cox regression model and subsequently validated. Additionally, the relationships between the identified HGLRG signature and multiple metabolites, drug sensitivity and various cell clusters were explored. Results: Thirteen genes were identified as constituting the HGLRG signature. Using this signature, we established predictive models, including HGLRG risk scores and nomogram and Cox regression models. The stratification of patients into high- and low-risk groups based on HGLRG risk scores showed a better prognosis in the latter. The high-risk group displayed increased sensitivity to cytotoxic drugs and targeted inhibitors. The expression of the HGLRG BGN displayed a strong correlation with amino acids and lipid metabolites. Notably, a significant difference in immune infiltration, such as that of M1 macrophages and CD8 T cells, was correlated with the HGLRG signature. The abundant DUSP1 within the mesenchymal components was highlighted by single-cell transcriptomics. Conclusion: The innovative HGLRG signature demonstrates efficacy in predicting survival and providing a practical clinical model for gastric cancer. The HGLRG signature reflects the internal metabolism, drug responsiveness, and immune microenvironment components of gastric cancer and is expected to boost patients’ response to targeted therapy and immunotherapy.

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PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress

Cited by 10 publications

References 49 publications

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer

Development of a Comprehensive Gene Signature Linking Hypoxia, Glycolysis, Lactylation, and Metabolomic Insights in Gastric Cancer through the Integration of Bulk and Single-Cell RNA-Seq Data

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