Oncogenic KRAS induces arginine auxotrophy and confers a therapeutic vulnerability to SLC7A1 inhibition in non-small cell lung cancer
The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypo-acetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Cancer research - (2024) vom: 19. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gai, Xiameng [VerfasserIn] |
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Date Revised 19.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1158/0008-5472.CAN-23-2095 |
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| PPN (Katalog-ID): |
NLM36992469X |
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| 520 | |a The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypo-acetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC | ||
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| 700 | 1 | |a Liu, Yingluo |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Xiaojing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Luoyi |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yize |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Yiyang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Liya |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Yixian |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Shuai |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Siyuwei |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Xiaoyang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Geng, Meiyu |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Pu, Congying |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Min |e verfasserin |4 aut | |
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