Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9
BACKGROUND: Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism.
METHODS: The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model.
RESULTS: We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth.
CONCLUSION: Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Cancer biology & therapy - 25(2024), 1 vom: 31. März, Seite 2304161 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yan, Fei [VerfasserIn] |
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| Links: |
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| Themen: |
Hypoxia |
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| Anmerkungen: |
Date Completed 06.02.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/15384047.2024.2304161 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367173875 |
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| 245 | 1 | 0 | |a Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9 |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 06.02.2024 | ||
| 500 | |a Date Revised 11.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism | ||
| 520 | |a METHODS: The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model | ||
| 520 | |a RESULTS: We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth | ||
| 520 | |a CONCLUSION: Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Non-small cell lung cancer | |
| 650 | 4 | |a SOX9 | |
| 650 | 4 | |a hypoxia | |
| 650 | 4 | |a lactylation | |
| 650 | 4 | |a metastasis | |
| 650 | 4 | |a stemness | |
| 650 | 7 | |a SOX9 protein, human |2 NLM | |
| 650 | 7 | |a SOX9 Transcription Factor |2 NLM | |
| 700 | 1 | |a Teng, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaoyou |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Yuejiao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chunyi |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xia |e verfasserin |4 aut | |
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